For Historical Reference Onlysickle CELL DISEASE M NGMN and ANAGEMENT T EAYOF HERAPY S ICKLE C ELL D ISEASE

Division of Blood Diseases and Resources ainlHat ug and Blood Institute Lung, National Heart,

M ANAGEMENT

ArchiveAND THERAPY OF for historical Reference OnlySICKLE CELL DISEASE M NGMN AND ANAGEMENT T EAYOF HERAPY S ICKLE C ELL D ISEASE

U.S. DEPARTMENT OF HEALTH AND

HUMAN SERVICES 1995

Public Health Service National Institutes of Health NATIONAL INSTITUTES OF HEALTH NIH Publication No. 95-2117 December 1995 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

Archive for historical Reference Only

Discrimination Prohibited: Under provisions of applicable public laws enacted by Congress since 1964, no person in the United States shall, on the grounds of race, color, national origin, handicap, or age, be excluded from participation in, be denied the benefits of, or be subjected to discrimination under any program or activity (or, on the basis of sex, with respect to any education program or activity) receiving Federal financial assistance. In addition, Executive Order 11141 prohibits discrimination on the basis of age by contractors and subcontrac- tors in the performance of Federal contracts, and Executive Order 11246 states that no federally funded contractor may discriminate against any employee or applicant for employment because of race, color, religion, sex, or national origin. Therefore, the National Heart, Lung, and Blood Institute must be operated in compliance with these laws and Executive Orders.

M ANAGEMENT ArchiveAND THERAPY OF for historical Reference Only SICKLE CELL DISEASE

NIH PUBLICATION

NO. 96-2117

ORIGINALLY PRINTED 1984

PREVIOUSLY REVISED 1989

REVISED DECEMBER 1995

(THIRD EDITION)

NATIONAL INSTITUTES

OF HEALTH

National Heart, Lung,

and Blood Institute

Archive for historical Reference Only

Editors:: Clarice D. Reid, M.D. Director, Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Bethesda, Maryland

Samuel Charache, M.D. Emeritus Professor of Medicine and Pathology Johns Hopkins School of Medicine Baltimore, Maryland

Bertram Lubin, M.D. Director of Medical Research Children’s Hospital Medical Center Oakland, California

Co-Editors: Cage Johnson, M.D. Professor University of Southern California Los Angeles, California

Kwaku Ohene-Frempong, M.D. Director, Comprehensive Sickle Cell Center The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

CONTENTSArchive for historical Reference Only

Preface ...... v Contributors ...... vii Introduction ...... 1 Chapter 1. Child and Adolescent Health Care Maintenance ...... 5 Chapter 2. Adult Health Care Maintenance ...... 13 Chapter 3. Patient Care Coordination ...... 17 Chapter 4. Psychosocial Management ...... 21 Chapter 5. Newborn Screening ...... 27 Chapter 6. Infection ...... 29 Chapter 7. Painful Events ...... 35 Chapter 8. Lung ...... 47 Chapter 9. Stroke ...... 53 Chapter 10. Transfusion ...... 59 Chapter 11. Splenic Sequestration and Transient Aplastic Crisis ...... 69 Chapter 12. Eye ...... 73 Chapter 13. Contraception and Pregnancy ...... 75 Chapter 14. Prenatal Diagnosis ...... 79 Chapter 15. Gallbladder and Liver ...... 83 Chapter 16. Leg Ulcers ...... 87 Chapter 17. Bones and Joints ...... 91 Chapter 18. Renal ...... 95

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Chapter 19. Priapism ...... 101 Chapter 20. Heart Archive ...... 105 Chapter 21. Surgery and Anesthesia ...... 109 Chapter 22.for Sickle historical Cell Trait ...... Reference ...... Only ...... 111 Chapter 23. Experimental Therapy ...... 113

PREFACE Archive for historical Reference Only

We are pleased to offer the third edition of the Prophylactic Penicillin Trial II, the Management and Therapy of Sickle Cell Multicenter Hydroxyurea Study, as well as Disease. According to all reports, previous epidemiological data derived from the editions have served both the lay and pro- Cooperative Study of Sickle Cell Disease fessional communities extremely well in (CSSCD). sorting out various approaches to health The forum for developing this booklet was maintenance and complications of patients unchanged from that used in producing with sickle cell disease. As in the past, this previous editions. After accepting assign- edition serves as a guide for the health ments to review the specific topics, a small care worker involved in the management group of pediatricians, nurses, hematolo- of patients with sickle cell disease. It repre- gists, and internists met in Bethesda and, at sents a collective summary of experiences the end of 1 day, had hammered out posi- with therapeutic regimens rather than the tions that could be agreed upon by most of by-product of controlled clinical trials. the participants. Each 5-year period sees Some users have referred to this booklet as fewer and fewer areas of disagreement, the Bible and others a “cookbook,” and although it is unlikely that everyone pres- while neither is an accurate descriptor, the ent will proceed exactly along the same contributors hope that the real use is some- pathway. We encourage you to use this where in between. During this past 5-year booklet as you see fit and to share it with interval, progress in clinical management of your students, house staff, and clinical col- sickle cell disease has been incredible. leagues. We invite questions and comments Most of the chapters in this edition have and hope that you will feel free to contact been totally rewritten or updated to reflect the contributors who have made their tele- these advances and modifications in prac- phone numbers and addresses available. tices and to describe the published results of clinical research. These include findings from the Preoperative Transfusion Study, Clarice D. Reid, M.D.

Archive for historical Reference Only

CONTRIBUTORSArchive for historical Reference Only

Rita Bellevue, M.D. Ann Earles, R.N., P.N.P. New York Methodist Hospital Children’s Hospital Oakland 506 Sixth Street Department of Hematology/Oncology Brooklyn, NY 11215-9008 747 52nd Street 718/780-5643 Oakland, CA 94609 718/780-3529 FAX 510/428-3453 510/450-5647 FAX Lennette J. Benjamin, M.D. Montefiore Medical Center Stephen Embury, M.D. 111 East 210th Street San Francisco General Hospital Central Building #221 Building 100, Room 263 Bronx, NY 10467 1001 Potrero Avenue 718/920-7373 San Francisco, CA 94110 718/798-5095 FAX 415/206-8574 415/206-3332 FAX Oswaldo Castro, M.D. Howard University Cage Johnson, M.D. 2121 Georgia Avenue, N.W. University of Southern California Washington, D.C. 20059 2025 Zonal Avenue - RMR 304 202/806-7930 Los Angeles, CA 90033 202/806-4517 FAX 213/342-1259 213/342-1255 FAX Samuel Charache, M.D. The Johns Hopkins University Thomas Kinney, M.D. Department of Laboratory Medicine Duke University Medical Center 2006 Sulgrave Avenue Erwin Road - 5417 Duke North Baltimore, MD 21209 Durham, NC 27710 410/466-6405 919/681-3395 410/466-4330 FAX 919/681-2714 FAX

Wesley Covitz, M.D. Mabel Koshy, M.D. Bowman Gray School of Medicine University of Illinois at Chicago Department of Pediatrics/Cardiology Room 1420 CSB 300 South Hawthorne Road 840 South Wood Street (M/C 787) Winston-Salem, NC 27103 Chicago, IL 60612 919/748-4627 312/996-5680 919/748-4204 FAX 312/996-5984 FAX

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Lawrence Lessin, M.D. Darlene Powars, M.D. Washington Hospital Center University of Southern California Medical The Cancer Institute Center 110 Irving Street, N.W.ArchiveDivision of Hematology/Oncology Washington, D.C. 20010 1129 North State Street 202/877-8112 Los Angeles, CA 90033 202/877-8113for FAX historical Reference213/226-3853 Only 213/226-5049 FAX Bertram Lubin, M.D. Children’s Hospital Medical Center of Clarice D. Reid, M.D. Northern California National Institutes of Health Department of Hematology/Oncology National Heart, Lung, and Blood Institute 747 52nd Street Division of Blood Diseases and Resources Oakland, CA 94609 Two Rockledge Centre 510/428-3502 MSC 7950 - Room 10160 510/528-3608 FAX 6701 Rockledge Drive Bethesda, MD 20892-7950 Scott Miller, M.D. 301/435-0080 SUNY-Brooklyn 301/480-0867 FAX 450 Clarkson Avenue - Box 49 Brooklyn, NY 11203 Wendell Rosse, M.D. 718/270-1692 Duke University Medical Center 718/270-1985 FAX Department of Medicine Hematology/Oncology Paul F. Milner, M.D. Post Office Box 3934 Medical College of Georgia Durham, NC 27710 Sickle Cell Clinic - FK 100 919/684-3724 Augusta, GA 30912 919/681-8477 FAX 706/721-2171 706/721-4575 FAX Jeanne A. Smith, M.D. Comprehensive Sickle Cell Center Kwaku Ohene-Frempong, M.D. Harlem Hospital - Columbia University The Children’s Hospital of Philadelphia 506 Lenox Avenue - Suite 6146 Comprehensive Sickle Cell Center New York, NY 10037 324 South 34th Street 212/939-1701 Philadelphia, PA 19104 212/939-1692 FAX 215/590-3423 215/590-2499 FAX Gwendolyn Swinson, R.N. Bronx Comprehensive Sickle Cell Center Orah Platt, M.D. Montefiore Medical Center Children’s Hospital Medical Center, Boston 111 East 210th Street Division of Hematology/Oncology Bronx, NY 10467 Enders Research Building - Room 761 718/920-7373 320 Longwood Avenue 718/798-5095 FAX Boston, MA 02115 617/355-6347 617/355-6081 FAX

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Elliott Vichinsky, M.D. Doris Wethers, M.D. Children’s Hospital Oakland St. Luke’s Roosevelt Hospital Center 747 52nd Street Sickle Cell Program Oakland, CA 94609Archive1111 Amsterdam Avenue 510/428-3651 New York, NY 10025 510/450-5647 FAX 212/523-3103 for historical Reference212/523-1839 Only FAX Winfred Wang, M.D. St. Jude Children’s Research Hospital Department of Hematology/Oncology 332 North Lauderdale Memphis, TN 38101 901/495-3497 901/521-9005 FAX

Archive for historical Reference Only

INTRODUCTIONArchive for historical Reference Only

Sickle cell disease is a generic term for a the thalassemia gene, the individual has group of genetic disorders characterized by Sβ+ thalassemia (Sβ+ thal). In the case of the predominance of hemoglobin S (Hb S). hemoglobin (SC disease), the individual These disorders include sickle cell anemia, has two abnormal beta globin genes, βS the sickle beta thalassemia syndromes, and and βC, and makes two abnormal hemoglo- hemoglobinopathies in which Hb S is in bins, Hb S and Hb C. Because the alpha association with another abnormal hemoglobin genes are located on a different globin that not only can participate in the chromosome from the beta genes, a patient formation of hemoglobin polymers but also with sickle cell anemia can independently is present in sufficient concentration to inherit an alpha globin gene abnormality. A enable the red cells to sickle. Examples of common condition in people of African the latter disorders include hemoglobin SC descent that has clinical significance for disease, hemoglobin SD disease, and patients with a sickle cell disorder is the hemoglobin S OArab disease. The sickle cell deletion of two of the four alpha globin disorders are found in people of African, genes, resulting in alpha thalassemia trait. Mediterranean, Indian, and Middle Eastern In contrast to these diseases is sickle cell heritage. In the United States, these disor- trait. Individuals with sickle cell trait (Hb ders are most commonly observed in AS) have a normal beta globin gene (βA) African Americans and Hispanics from the and a βS globin gene, resulting in the pro- Caribbean, Central America, and parts of duction of both normal hemoglobin A and South America. hemoglobin S, with a predominance of Hb Sickle cell disorders are best classified by A. Their red blood cells sickle only under genotype. The type of hemoglobin pro- unusual circumstances such as marked duced is determined by the two beta glo- hypoxia and the hyperosmolar environ- bin genes located on chromosome 11 and ment of the renal medulla (resulting in the four alpha globin genes located on hyposthenuria). chromosome 16. Individuals who are There are two cardinal pathophysiologic homozygous for the sickle beta globin features of sickle cell disorders: chronic gene (βS) have sickle cell anemia (SS dis- hemolytic anemia and vaso-occlusion ease). Individuals with sickle beta thal- (which results in ischemic tissue injury). assemia have a βS gene and a gene for Hemolytic anemia may be related to beta thalassemia. If no beta globin is pro- repeated cycles of sickling and unsickling, duced by the beta thalassemia gene, the which interact to produce irreversible red individual has Sβo thalassemia (Sβo thal). If cell membrane changes, red cell dehydra- some normal beta globin is produced by tion, and erythrocyte destruction. Tissue

injury is usually produced by hypoxia sec- distinguishing between sickle cell anemia ondary to the obstruction of blood vessels and some of the sickle beta thalassemia by an accumulation of sickled erythrocytes. syndromes, including Sβo thal and sickle The organs at greatestArchive risk are those with cell trait, in association with hereditary venous sinuses where blood flow is slow persistence of fetal hemoglobin (S HPFH). and oxygen tension and pH are low It is important that distinctions be made (spleen andfor bone historical marrow) or those with Reference a because these Onlydisorders differ markedly in limited terminal arterial blood supply (eye, their clinical expression. For example, head of the femur and humerus). The lung, symptoms of patients with Hb Sβo thal are as the recipient of deoxygenated sickle similar to those of Hb SS; patients with cells that escape from the spleen or bone Hb Sβ+ thal have less associated symp- marrow, may be at special risk for vaso- toms, and those with Hb S HPFH are occlusion and infarction. No tissue or organ asymptomatic and not anemic. is spared from this injury. Symptoms of the Patients with SS or Sβo thal disease or S hypoxic injury may be either acute (e.g., HPFH all have similar electrophoretic pat- painful events, acute chest syndrome) or terns. Mean corpuscular volume (MCV) is insidious in onset (e.g., aseptic necrosis of definitely decreased in thalassemia syn- the hips, sickle cell retinopathy). The effects dromes and is somewhat decreased in S of acute and chronic tissue injury may ulti- HPFH. Measurement of Hb A and Hb F mately result in failure of organs like the 2 may help in distinguishing between these kidney, particularly as the patient ages. conditions. In general, Hb A2 levels are ele- An additional and less recognized problem vated above 3.5 percent in Sβo thal and are is that sickle cell patients live under consid- low in patients with S HPFH. Hb F levels erable psychosocial stress. Not only do are generally higher in the sickle beta thal- they experience stresses common to other assemic disorders than in SS disease, painful chronic illnesses, but they must also although there is considerable overlap cope with the unpredictable nature of their between these diagnostic groups. In those illness. The recurrent and unpredictable instances where S HPFH is suspected, mea- nature of the disease can adversely affect surement of Hb F in the parents and/or both school and work attendance and has siblings can be valuable. the potential of reducing the patient’s sense of self-esteem. The diagnosis of sickle cell disease cannot and must not be made from either a sickle Appropriate counseling and management cell preparation or solubility test because requires definitive diagnosis. The diagnosis neither of these tests will reliably distin- of sickle cell disease is primarily based on guish sickle cell trait from sickle cell dis- hemoglobin electrophoresis. In those ease. The diagnosis of a specific sickle cell instances where Hb S is found in associa- disorder can be readily established through tion with another abnormal hemoglobin an analysis of the alpha and beta globin such as Hb C, the diagnosis can be made gene complex by using techniques of mo- by electrophoresis alone. In those lecular biology; however, these are not usu- instances, however, when the electrophore- ally required. The clinician should rely on sis reveals only Hb S, Hb F (fetal hemoglo- the clinical history, blood counts, peripher- bin), and Hb A2, there can be difficulty in al blood smear, hemoglobin electrophoresis

with measurement of the minor hemoglo- Table 1 summarizes the relationships bins A2 and F, and, when available, family between the clinical severity, blood counts, studies that include hemoglobin elec- peripheral smear, Hb A2 levels, and Hb S trophoresis andArchive measurement of Hb A and levels for the more common sickle cell 2 Hb F. disorders.

Tablefor 1 historical Reference Only Clinical and Hematologic Findings in the Common Variants of Sickle Cell Disease After the Age of 5 Years*

HEMOGLOBIN ELECTROPHORESIS HEMATOLOGIC VALUES

Disease Clinical S F A2 A Hb Retic MCV RBC Group Severity (%) (%) (%) (%) g/dL (%) (fl) Morphology SS Usually marked >90 <10 <3.5 0 6-11 5-20 >80 sickle cells nrbc normochromia anisocytosis poikilocytosis target cells Howell-Jolly bodies

Sβo Thal Marked to >80 <20 >3.5 0 6-10 5-20 <80 sickle cells moderate nrbc hypochromia microcytosis anisocytosis poikilocytosis target cells

Sβ+ Thal Mild to >60 <20 >3.5 10-30 9-12 5-10 <75 no sickle cells moderate hypochromia microcytosis anisocytosis poikilocytosis target cells SC Mild to 50 <5 † 0 10-15 5-10 75-95 ”fat” sickle cells moderate anisocytosis poikilocytosis target cells S HPFH Asymptomatic <70 >30 <2.5 0 12-14 1-2 <80 no sickle cells anisocytosis poikilocytosis rare target cells Hematologic values are approximate. *For findings in younger children, see Brown AK, Sleeper LA, Miller ST, et al. Reference values and hematological changes from birth to five years in patients with sickle cell disease. Arch Pediatr Adolesc 1994;48:796-804. † = 50 percent Hb C. nrbc = nucleated red blood cells. There is tremendous variability between disease groups and between individual patients of the same group, particularly regarding clinical severity.

CHAPTER 1 CHILD ANDArchiveADOLESCENT HEALTH CARE MAINTENANCE for historical Reference Only

During the past several decades, there have education that is age appropriate, realizing been substantial advances in the manage- that the child’s need for information will ment of patients with sickle cell disease. change with age. Providers who speak For example, infant morbidity and mortality only to the parents and fail to incorporate from overwhelming pneumococcal infec- the child or adolescent into the manage- tion have been reduced by the administra- ment plan will foster dependency in the tion of prophylactic antibiotics, and some child, ultimately hindering the transition to individuals have been cured of their dis- adulthood. The provider also must be ease by bone marrow transplantation. knowledgeable about existing medical and Enhanced testing of blood products for psychosocial resources within the commu- infectious agents and more careful attention nity and assist the patient in accessing to crossmatching for minor red blood cell these services when appropriate. antigens have reduced complications from blood transfusion. Comprehensive sickle DEFINITIVE DIAGNOSIS cell programs can reduce morbidity and When a newborn’s screening test indicates mortality by providing easily accessible “sickle cell disease,” it is the primary physi- health care services administered by indi- cian’s responsibility to either establish a viduals knowledgeable about the disease definitive diagnosis or to refer the patient and its complications. As a result of these to a pediatric hematologist for this purpose. advances, children with sickle cell anemia As discussed in Chapters 1 and 5, establish- have about an 85 percent probability of ing a definitive diagnosis requires accurate reaching 20 years of age. characterization of the hemoglobin pheno- At the crux of effective health care mainte- type and correlation of the phenotype with nance is a strong patient-provider relation- the clinical history, blood counts, and red ship built on trust, respect, open communi- blood cell morphology. Recent advances in cation, and mutual understanding. The molecular biology techniques have identi- child and family should be encouraged to fied many variations in the beta globin be active participants in the health care gene area (beta globin gene haplotype) program, to be candid in expressing their that may modify the clinical expression of concerns, and to work closely with the sickle cell disease. Studies of the child’s provider in all areas. In turn, the provider parents are useful in establishing a defini- must be sensitive to the child’s development tive diagnosis but must be undertaken with and be willing to offer counseling and caution as the tests may disclose mistaken

paternity. As in all inherited disorders, thor- of visits should depend on the needs of the ough counseling of the mother is recom- child and family. During the first 2 years of mended before performing extensive family life, health care maintenance visits should testing, and family testingArchive should not be be scheduled concurrently with needed performed if the mother objects. immunizations. Older patients who are doing well can be seen semi-annually. Once the definitive diagnosis is established, for historical ReferenceChildren also shouldOnly be seen within a short the parents should be provided with time after a hospitalization or emergency appropriate education and counseling room visit so the physician can review the about the specific form of sickle cell dis- situations that may have precipitated the ease affecting their child. Providers must event and make any necessary changes in explain things carefully, avoiding medical the treatment plan. jargon and allowing ample time for questions. Practitioners should not “overload” Immunizations should be administered parents by providing them with too much according to schedules recommended by detail during initial visits. More than one either the American Academy of Pediatrics counseling/education session is required to or the American Academy of Family ensure that parents adequately understand Practice. In addition, all children with the information. A practitioner should not sickle cell disease should be immunized hesitate to refer the patient and family to a against hepatitis B virus and should specialist for counseling. Many community- receive the polyvalent pneumococcal vac- based sickle cell organizations are available cine at age 2 years, with a booster at age to help with patient education and the 5 years. Seasonal influenza vaccines are acquisition of social services. recommended. The definitive diagnosis should be record- Dietary counseling is an important part of ed on the child’s immunization record and routine health care. Mothers should be in other key medical records. A copy of the encouraged to breastfeed their infants, diagnostic information also should be given although iron-fortified formulas are an to the parents so that information can be alternative. Supplemental iron should not shared with other health professionals be prescribed unless the patient is docu- involved with the infant’s care. mented to have reduced iron stores by specific assessments of the serum ferritin level MAINTENANCE HEALTH CARE or measurement of serum iron and iron- SERVICES binding capacity. Children with hemoglobin SC disease are often microcytic in the General Issues absence of iron deficiency or concomitant Health care maintenance services for chil- alpha thalassemia. Similarly, the incidence dren and adolescents with sickle cell dis- of alpha thalassemia trait is quite high in ease include those services provided to the African-American population and may healthy children and services specifically produce microcytosis in the absence of provided for sickle cell disease. Routine iron deficiency. Routine administration of services include immunizations and dietary supplementary folic acid may not be neces- counseling as well as education about sary unless the dietary history reveals inad- preventive health measures. The frequency equate folate intake. Particular attention

should be paid to the diet if education, Sickle Cell-Specific Issues unmet economic needs, or cultural patterns In addition to the general health mainte- place the child at risk for dietary deficiencies. Archivenance issues, there are health maintenance All children, including those with sickle cell issues specific for sickle cell disease. These disease, need regular dental care. include the need for parents to learn spe- Supplementalfor historical fluoride given topically, Reference in cific physical Only assessment skills, to adminis- vitamins, or in the drinking water, should ter prophylactic antibiotics, to implement be provided when indicated. Cleaning and measures that minimize the risk of vaso- dental fillings do not require special care. occlusive complications, and to use anal- Operative procedures such as extractions gesics and comfort measures to minimize and root canal therapy should be preceded pain. During health maintenance visits, and followed by standard rheumatic fever providers also should carefully review the antibiotic prophylaxis to lessen the risk of history and physical examination for evi- bacteremia/sepsis. If general anesthesia is dence of organ dysfunction. required, the child should be hospitalized, When performing the physical examina- and preoperative transfusion should be tion, providers should pay attention to considered if the surgery is extensive (see growth parameters and physical develop- Chapter 10). ment. Physical growth and sexual matura- Other health care maintenance services tion are delayed in sickle cell anemia include routine hearing and vision screen- patients compared with normal children, ing and periodic skin tests for tuberculosis. but the child eventually will “catch up” Because of the ocular complications of during the late teenage years. Common sickle cell disease, adolescents and adults physical findings in children with sickle should be seen annually by an ophthalmol- cell disease include mild generalized ogist. Providers must also counsel patients lymphadenopathy, functional systolic mur- and parents about the adverse health murs, and slight hepatic enlargement. effects of illicit drugs, including tobacco Splenomegaly is often seen in infants and and alcohol. Teenagers should be coun- young children but is uncommon in children with SS disease and Sβo seled about safe sex practices, including thalassemia after age 6 years. Splenomegaly, however, abstinence. If sexually active, they should is frequently observed in patients of all be encouraged to use condoms to prevent ages with Hb SC disease and Sβ+ thal- getting sexually transmitted diseases, assemia. Because limitation of motion and including acquired immunodeficiency syn- pain are common signs of aseptic necrosis, drome (AIDS). Adolescent girls should the range of motion of the hips of older receive additional counseling on birth con- children and adolescents should be trol practices and be provided with birth assessed. Scleral icterus is another common control pills or other effective contracep- physical finding. Because children and ado- tives when requested, given that there are lescents are often teased about their “yel- no specific contraindications (see Chapter low eyes,” they should be taught the 13, Contraception and Pregnancy). nature of this characteristic and reassured

that it will not affect their visual acuity and need access to fluids while at school and does not necessarily reflect liver disease. will also need to be excused periodically from class to use lavatory facilities. Blood counts shouldArchive be done frequently during the first year of life to establish the One of the major advances in the care of patient’s baseline, but after 12 months of infants with sickle cell anemia has been the age, the forhemoglobin historical and hematocrit are Referencerecognition that Only oral penicillin given twice relatively stable and need to be checked a day will reduce morbidity and mortality only once or twice a year in uncomplicated from pneumococcal infections. Prophylactic patients. For patients who are doing well, penicillin is recommended for all patients an annual urinalysis and measurement of with SS disease and Sβo thal until they are blood urea nitrogen (BUN), serum creati- 5 years of age. For patients who are aller- nine, and liver enzymes are adequate for gic to penicillin, erythromycin ethyl succi- monitoring the patient for evidence of nate (20 mg/kg) divided into two daily organ damage. Before the administration of doses can provide adequate prophylaxis. the first transfusion, the patient’s red blood The importance of administering the pro- cell antigens should be determined and phylactic antibiotics should be addressed at recorded in the patient’s permanent medical all visits because parents may become lax record. in dispensing this essential treatment over Specific physical assessment skills that time. Penicillin may be prescribed in either should be taught to parents include taking liquid or tablet form; finely crushed pills the body temperature and assessing respi- may be given to young children. Pills have ratory effort, degree of pallor, and spleen an important advantage over liquid peni- size. Parents of children who have an cillin preparations because pills are stable enlarged spleen should be taught to pal- for years compared with liquid forms of pate the spleen and may be given a tongue penicillin that must be discarded after 2 depressor that indicates the level at which weeks. An alternative to oral penicillin is injections of 1.2 million units of long-acting the spleen extends below the left costal ® margin in the mid-clavicular line. The par- Bicillin every 3 weeks. A recently con- ent can use this “spleen stick” to determine cluded randomized trial demonstrated that if the spleen size has changed and can pro- penicillin prophylaxis may be safely vide the stick to other health care providers stopped after the patient’s fifth birthday. who assess the child. The skin around the Concerns regarding the development of ankles of adolescents should be examined penicillin-resistant pneumococcal infections carefully for ulcers, and patients should be should not prevent the use of prophylactic reminded to avoid trauma to the lower penicillin, but appropriate measurements of extremities because this may precipitate antibiotic sensitivity are required in treating ulcerations. Parents should also be told that patients who have pneumococcal infections the child may have repeated episodes of (see Chapter 6). enuresis or nocturia as a result of the renal The role of prophylactic penicillin in SC concentrating defect and should be provid- disease and Sβ+ thal is less well estab- ed with suggestions on how to manage this lished. Although these latter two groups of rather difficult problem. Parents should patients are not at the same risk as children remind school officials that their child will with SS disease for overwhelming infection

by encapsulated organisms because they collaboration and communication between have better preservation of splenic func- primary care providers and consultant tion, a significant number of pneumococcal specialists. infections haveArchive been reported. Regardless of whether a sickle cell patient is receiving Adolescents prophylactic antibiotics, these patients shouldfor be evaluatedhistorical promptly when Reference they Those who Only treat adolescents should realize develop a fever greater than 38.5 oC that these individuals are coping with a (101 oF) (see Chapter 6, Infection). very difficult time in their life, and the mul- tiplicity of problems confronting healthy Parents and patients should be instructed adolescents also exists for individuals with in the proper use of analgesia. Fear of sickle cell disease. All health professionals addiction may prevent parents from admin- who care for adolescents must be particu- istering adequate analgesics to their chil- larly attuned to the range of their problems dren. Similarly, older patients may under- and to the local resources available for medicate themselves for fear of becoming assistance (see Chapter 4). Compliance addicted to the analgesic (see Chapter 7, with medication regimens and clinic visits Painful Events). Discussing these issues can be a problem at any age but is a par- with the patient and parents and using ticular problem in this age group. Health nonaddictive analgesics where possible care providers should identify ways to should minimize the risk of drug depen- motivate such patients, including peer sup- dency. Providers can explore various ancil- port groups and one-on-one guidance by a lary measures with the patient to assist knowledgeable staff member. with pain management, including biofeed- back and relaxation techniques. The The transition from a pediatric medical set- provider can also address health care prac- ting to the adult care setting is often diffi- tices that minimize the risk of painful cult for the patient. Ideally, adolescents in events such as maintaining adequate hydra- the pediatric setting should be given assis- tion, treating infections promptly, and tance in learning how to use the adult care avoiding temperature extremes. Patients facility and be introduced to their new can often predict that a painful event is providers by those who have cared for about to happen and can frequently help them as children (see Chapter 3, Patient themselves by implementing treatment Care Coordination). In some hospitals, this before the pain becomes too severe. transition is greatly eased by holding con- Deterioration in school performance or current pediatric/adolescent/adult sickle changes in behavior may be early signs of cell clinic sessions. cerebrovascular disease and should be evaluated promptly by physicians knowledgeable COUNSELING about sickle cell disease. In addition to genetic counseling, sickle Primary care providers should identify cell patients and their families may need physicians with expertise in sickle cell dis- counseling in academic and vocational ease to assist them in managing sickle cell guidance as well as counseling related to patients under their care. Cost-effective recreational activities and travel. The basic care can be provided when there is close premise, however, is that parents should

treat their affected child as normally as provided by the Americans With possible. Parents should encourage activi- Disabilities Act. ties that foster self-esteem and self-reliance. A positive self-imageArchive and a feeling of self- Recreation and Travel worth will help children and adolescents to cope more effectively with their illness. There is often a need to provide counsel- for historical Referenceing in the area Only of recreation and physical activities. Patients should be encouraged to Academic and Vocational get regular exercise. School-age children Counseling should participate in physical education Providers should be prepared to counsel classes, but they should be allowed to rest teachers and other school officials as well if they tire, and they should be encouraged as patients. Narcotic analgesic usage and to drink fluids after exercise. The potential repeated absences may impair school per- risks of recreational activities that involve formance, necessitating the need for spe- strenuous exertion should be discussed cialized tutoring or the development of an with the patient. Patients with sickle cell individualized educational plan. Unless disease should dress warmly for cold impaired by cerebrovascular disease, chil- weather and should avoid direct exposure dren with sickle cell disease have the usual to cold temperatures, including swimming range of intelligence and should be in cold water. Children and adolescents encouraged to develop their full potential. should engage in competitive athletics with With additional tutoring or other assistance caution because it is difficult to heed the to compensate for time lost from school, signs of fatigue in the heat of competition, they can often remain at grade level. and the team may find it difficult to replace Appropriate counseling and anticipatory an athlete sidelined by illness. guidance may minimize academic difficulties. Children with sickle cell disease may bene- Vocational counseling is very important for fit from a summer camping experience, adolescents and adults with sickle cell dis- either in an appropriate regular camp or ease. Gainful employment is possible, through participation in a special camp for despite the unpredictable nature of vaso- children with sickle cell disease. If the occlusive complications. The adoption of camp staff members are knowledgeable flexible work hours is an example of a about the disease and comfortable with the strategy that will help patients in the work- care of these children, the camper can force. Referral to community resources, learn self-reliance and share experiences including school guidance and vocational with other children about sickle cell dis- rehabilitation counselors, is another way to ease while having fun. Health care assist the patient in assessing and obtaining providers and others who attend camp goals. Introducing children and adolescents with sickle cell children typically find this a to adults with sickle cell disease who have rewarding experience. successfully coped with their illness has a Patients and families often seek advice on very positive effect. Health care providers the best methods of travel. Flying in a pres- should be familiar with legal protection surized aircraft usually poses no special against discrimination in the workplace, problems for sickle cell patients, provided

that fluids are liberalized and the patient Gill F, Sleeper L, Weiner S, et al. Clinical dresses warmly to accommodate for the events in the first decade in a cohort of low humidity and cool temperature of the infants with sickle cell disease. Blood aircraft. On theArchive other hand, air travel above 1995;86(2):776-83. 15,000 feet in nonpressurized planes can Leiken SL, Gallagher D, Kinney TR, et al. inducefor vaso-occlusive historical complications. Reference Land Mortality Only in children and adolescents with travel by bus or automobile is not associat- sickle cell disease. Pediatrics 1989;84:500-8. ed with any increased risk of sickle cell- related complications, although frequent Pearson HA, Gallagher D, Chilcote R, et al. rest and refreshment stops should be Developmental pattern of splenic dysfunc- included in the travel plans. Patients should tion in sickle cell disorders. Pediatrics be encouraged to consult their physician 1985;76:392-7. before traveling and should be advised to Platt OS, Rosenstock W, Espeland M. carry with them specific medical informa- Influence of sickle hemoglobinopathies on tion that includes their diagnosis, baseline growth and development. N Engl J Med hematologic values, a list of current med- 1984;311:7-12. ications, and the name and telephone num- US Department of Health and Human ber of their physician. Providers should Services, Public Health Service, Sickle Cell give their patients the names of physicians Disease Guideline Panel. Sickle cell dis- or care facilities to contact in the event of ease: screening, diagnosis, management, problems. counseling in newborns and infants. Clinical Practice Guideline Number 6. BIBLIOGRAPHY Rockville, Maryland: Agency for Health Brown AK, Sleeper LA, Miller ST, et al. Care Policy and Research, 1993; AHCPR Reference values and hematological publication no. 93-0562. changes from birth to five years in patients Zarkowsky HS, Gallagher D, Gill FM, et al. with sickle cell disease. Arch Pediatr Bacteremia in sickle hemoglobinopathies. J Adolesc Med 1994;148:796-804. Pediatr 1986;109:579-85. Falletta JM, Woods RM, Verter JI, et al. Sickle Cell Pamphlets for Parents: Discontinuing penicillin prophylaxis in children with sickle cell anemia. J Pediatr 1. A Parents’ Handbook for Sickle Cell 1995;127(5):685-90. Disease. Part I, Birth to Six Years of Age. By Shelly Lessing, M.S., Elliott Farber M, Koshy M, Kinney TR. Vichinsky, M.D., Editors. Children’s Cooperative study of sickle cell disease: Hospital, Oakland Sickle Cell Center. demographic and socioeconomic character- Copyright 1990. State of California, istics of patients and families with sickle Department of Health Services Genetic cell disease. J Chron Dis 1985;36:495-505. Disease Branch, Revised 1991. Gaston MH, Verter JI, Woods G, et al. 2. Sickle Cell Disease in Newborns and Prophylaxis with oral penicillin in children Infants. A Guide for Parents. U.S. with sickle cell anemia. N Engl J Med Department of Health and Human 1986;314:1593.

Services. Public Health Service, Agency Department. St. Jude Children’s for Health Care Policy and Research, Research Hospital, Memphis, 1993. Tennessee. Mid South Sickle Cell ArchiveCenter. P.O. Box Suite 235, 1 Children 3. Your Child and Sickle Cell Disease. By Plaza, Memphis, Tennessee 38103. Sara Day, R.N. Produced by the Biomedicalfor Communicationshistorical Reference Only

CHAPTER 2 ADULT HArchiveEALTH CARE MAINTENANCE for historical Reference Only

Many patients can live for long periods INITIAL PATIENT VISIT without experiencing acute or severe exac- During the initial patient visit, a complete erbations of sickle cell disease. Increased medical history should be taken, and a awareness of the disease’s complications physical examination should be performed. and improved use and availability of health A patient should have a complete blood care are positive contributors to patient count, reticulocyte count, and hemoglobin longevity and productivity. Contrary to previous estimates that one-half of all sickle electrophoresis if this information is not cell disease patients die before age 20 already available. Laboratory tests, includ- years, about 90 percent of patients now ing urinalysis, liver function, urea, creati- survive past that age. Recent studies indi- nine, electrolytes, and chest x-ray, should cate that the mean age at death for SS also be obtained. Certain laboratory tests, patients is 42 years for males and 48 years although not routinely performed, may be for females. Most patients with SC and Sβ+ indicated by the presence of specific com- thalassemia can be expected to reach age plications. These tests include screening for 70 years and older. Many patients live a red cell antibodies, measurement of arterial full life, and patients age 50 years now blood gases, pulmonary function tests, constitute a large segment of the adult electrocardiograms (EKGs), studies to population with sickle cell disease. detect the presence of gallstones, and radiographs or magnetic resonance imaging Common practices and approaches to opti- (MRI) scans of the femoral and humeral mal health care maintenance of adults are heads to detect aseptic necrosis. Previous reviewed in this chapter, with an emphasis medical records should be requested as on developing a useful operational strategy well. If the patient has never received the for clinicians. Health maintenance includes pneumococcal vaccine, immunization prevention, early recognition and treatment should be offered. of complications, and continuing patient education. In contrast to the stress of acute Patients with sickle cell disease are at high crises, well-patient visits provide a better risk for developing sickle cell retinopathy. psychological setting for the development Patients should see an ophthalmologist for of effective doctor-patient relationships and retinoscopy; the ophthalmologist should effective coping skills. The development conduct followup examinations of patients of such relationships may result in fewer diagnosed with significant proliferative visits to the emergency room and fewer retinopathy, at regular intervals. hospitalizations.

Also during the initial visit, health providers control should be addressed, and the should assess the patient’s understanding patient’s spouse or partner probably should of the disease and its complications (see be included in these discussions (see “Patient Education” Archivein Chapter 3, Patient Chapter 13, Contraception and Pregnancy). Care Coordination). Family planning and It is particularly important to instruct genetic counselingfor historical services should be dis-Referencepatients about Only how to respond to acute ill- cussed, and the availability of prenatal ness. They should be instructed to seek diagnosis should be mentioned when immediate care for events such as high appropriate (see Chapter 13, Contraception fever, productive cough, and symptoms of and Pregnancy). Asymptomatic patients acute anemia such as sudden dyspnea, often have a false feeling of security about weakness, or dizziness. Discussion with the their disease. They should be cautious par- patient should include the identification of ticularly regarding the choice of a profes- available means of transportation to the sion and jobs requiring strenuous exercise emergency room. Painful episodes should and exposure to high altitudes. initially be managed at home with rest, a warm environment, increased oral fluids, PATIENT FOLLOWUP VISITS and mild analgesia or other modalities of Most patients with sickle cell disease pain management (see Chapter 7, Painful should have regular medical evaluations Events). If pain persists or fever develops, approximately every 3 to 6 months; certain the patient should contact his or her physi- patients need to be seen more frequently cian or go to an emergency department. as symptoms dictate. Others, including The procedure to be followed for a partic- asymptomatic patients with SC disease or ular emergency department should be dis- Sβ+ thal, should be seen every 6 months. A cussed in detail; if a prior call from the blood count as well as a reticulocyte count physician can facilitate the visit, the patient should be performed, and a urinalysis and should know whom to call at night or on routine chemistry tests should be repeated weekends and holidays. annually. With advancing age, complica- Patients should keep a small supply of an tions such as chronic organ failure often intermediate strength oral narcotic anal- require more frequent visits and more gesic (codeine, hydrocodone, or oxy- extensive laboratory evaluations. codone) and should be instructed to use it Attention should be focused particularly on for attacks of pain that do not respond to abnormalities of renal function such as aspirin, acetaminophen, or ibuprofen. They renal tubular acidosis and hyperuricemia should be informed that most pharmacists (see Chapter 18, Renal). During initial and will not accept a telephone prescription for followup visits, it is important to discuss a narcotic and should be instructed on how the general nature and variability of the to obtain another supply. disease with the patient and to explain the Certain matters of general health care are significance of symptoms. Specifically, com- particularly important to patients with sick- plications such as gallstones, aseptic necro- le cell disease; for example, it is important sis, and priapism should be mentioned. for the physician to discuss the hazards of Also, the issues of childbearing and birth cigarette smoking and excessive alcohol

intake. Although strenuous exercise may to facilitate their studies. For instance, they have to be avoided in most patients, a should be encouraged to inform their edu- well-planned exercise program should be cation program director or their employer encouraged (seeArchive “Counseling” in Chapter 1, that they have sickle cell disease and that Child and Adolescent Health Care students with sickle cell disease may take Maintenance). longer to complete their academic program for historical Referenceor may requireOnly special considerations in Most patients eat poorly during painful completing their course of study. crises, and because patients with hemolytic anemia have an increased need for folic PSYCHOSOCIAL COUNSELING acid, daily supplements of 1 mg should be prescribed at those times. The danger of Intervention by a social worker or mental masking a vitamin B12 deficiency is small, health professional is often indicated for a but even young African-American patients variety of psychosocial concerns and prob- are at risk. There is no evidence that any lems that affect sickle cell patients and other form of vitamin supplementation is of their families. Physicians in private practice value in sickle cell disease. may not have direct access to the services of psychologists or social workers. Such The patient’s employment should also be services may be available, however, discussed. Arrangements for obtaining through local social service agencies. “doctor’s notes” after an absence from work, filling out forms, and refilling pre- The nurse’s role in the management of psy- scriptions should be outlined for all chosocial issues is equally important. The patients with a chronic disease. Medical responsibility of nurses—often the primary providers should be familiar with proce- providers of care and the health profes- dures for seeking legal assistance if work- sionals most often seen by patients— place discrimination because of disability is includes the integration of other profes- perceived. sionals into health care efforts and the identification of special patient needs. Also, VOCATIONAL GOALS nurses can provide psychosocial counseling, preventive health care information, Individuals with sickle cell disease can pur- and patient and community education (see sue a variety of vocations and professions, Chapter 3, Patient Care Coordination). and they should be encouraged to do so. There are very few vocational choices that DENTAL CARE should be discouraged, except jobs requiring strenuous physical exertion, exposure Dental procedures requiring local anesthe- to high altitudes, or extreme temperature sia can be performed in the dentist’s office variations (see Chapters 1 and 4). as with any other patient, but procedures Students should not be discouraged by rig- requiring general anesthesia necessitate orous academic programs or long courses hospitalization. The use of nitrous oxide as of study; instead, they should be encour- an anesthetic agent for office dental proce- aged and supported. However, individuals dures is controversial and requires consul- with sickle cell disease should be informed tation between the physician and dentist. of any special considerations that are needed The customary administration of at least 50

percent oxygen with nitrous oxide allevi- Efforts should be made to ensure deep ates the risk of sickling. Concentrations of breathing and coughing, to avoid atelectasis. less than 20 percent oxygen should be avoided. Patients shouldArchive be fully alert EXPERIMENTAL THERAPY before leaving the office. Prophylactic There has been no established method of antibiotics should be used with operations treatment for the prevention of vaso-occlu- such as extractionsfor historical or root canal therapy, Reference if Only sive pain crisis and other complications of there is a question of rheumatic heart sickle cell disease. A number of experimen- disease or mitral valve prolapse or if an tal therapeutic approaches, including use of orthopedic prosthesis has been implanted. hydroxyurea, erythropoietin combined with hydroxyurea, short-chain fatty acids (such SURGERY AND ANESTHESIA as butyrate derivatives), and clotrimazole, The question of prophylactic preoperative are currently under investigation (see blood transfusion is addressed in Chapter Chapter 23, Experimental Therapy). 10. Intraoperative overexpansion of blood volume should be prevented, particularly in BIBLIOGRAPHY patients whose cardiac status is precarious. Aluoch JR. The treatment of sickle cell dis- No special precautions are needed for local ease: a historical and chronological litera- or regional anesthesia such as a pudendal ture review of the therapies applied since block. Careful epidural anesthesia can be a 1910. Trop Geogr Med 1984:36(suppl):S1- good compromise for gynecologic or proc- S26. tologic procedures. Operation in a “blood- less field” with the use of tourniquets may Charache S. Treatment of sickle cell ane- be hazardous. If possible, an alternative mia. Ann Rev Med 1981;32:195-205. technique or prior exchange transfusion, or Embury SH, Hebbel RB, Mohandas N, both, should be used. With all types of Steinberg MH. Sickle cell disease: basic anesthesia, intraoperative hypothermia principles and clinical practice. New York: should be prevented. Raven Press, 1994. After surgery, it is extremely important to Platt OS, Brambilla DJ, Rosse WF, et al. ensure hydration and, at the same time, Mortality in sickle cell disease. Life prevent circulatory congestion. Adequate expectancy and risk factors for early death. records of the amount of intravenous and N Engl J Med 1994;330:1639-44. oral intake should be maintained; urine output and fluid drainage should be mea- Serjeant GR. Sickle cell disease. Oxford: sured and recorded, and patients should be Oxford University Press, 1992. weighed daily. Minor hyponatremia (130- Vichinsky EP, Johnson R, Lubin BH. 140 meq/L) can be tolerated but care Multidisciplinary approach to pain manage- should be taken to avoid hypernatremia ment in sickle cell disease. Am J Pediatr (see Chapter 21, Surgery and Anesthesia). Hematol Oncol 1982;4:328-33.

CHAPTER 3 PATIENT CArchiveARE COORDINATION for historical Reference Only

The complexities of sickle cell disease expected schedule of visits, routine tests, demand intricate coordination of health and immunizations should be carefully out- care services. Because of their unique edu- lined. Special procedures that are part of cational preparation, mid-level practitioners the standard of care such as EKGs, pul- (MLPs) (i.e., nurses, physician assistants monary function tests, neuropsychiatric (PAs), clinical nurse specialists, and nurse testing, and necessary immunizations practitioners) are best suited for assuming should be discussed. The patient or parent this responsibility. Discussion of patient must be able to demonstrate an under- care coordination; preventive health care; standing of these procedures before being home management, including pain man- asked to sign a consent form. agement and comfort measures; patient Preventive care also includes education education; and education of other health about recognizing acute and life-threaten- care providers will be included in this chap- ing events associated with sickle cell dis- ter. Inpatient, outpatient, and emergency ease. Early recognition and prompt report- department care also will be highlighted. ing of symptoms may prevent or minimize complications. The parents of children with PATIENT CARE COORDINATION sickle cell disease must be taught how to Because of the chronic nature of sickle cell use a thermometer and palpate the spleen, disease, multidisciplinary and subspecialty and they should be asked to demonstrate referrals are often necessary. The MLP may their ability to perform these procedures. serve as the liaison among the patient, the Reinforcing the need for prophylactic peni- primary care provider, and the specialist. cillin may improve compliance. In addition, All individual treatment plans must be the MLPs should talk with patients about developed with patient and parent partici- when to call for advice and when to seek pation to identify problem areas that may immediate medical attention. Transportation adversely affect compliance with required planning should be discussed before an care. Ongoing assessments are necessary emergency situation arises. to identify the need for referrals to other Age-appropriate education should continue professionals for further interventions. into adulthood along with an emphasis on preventive health care. The importance of PREVENTIVE CARE regular health care maintenance and visits At each visit, MLPs should emphasize the other than for episodic acute care cannot importance of regular health care examina- be overemphasized. Reviewing the symp- tions to patients during steady states. The toms of acute events and the significance

of early treatment of complications are pertinent information to the adult care crucial and can be provided by the MLP. practitioner.

PATIENT EDUCATIONArchiveEDUCATION OF OTHER HEALTH CARE PROVIDERS The complexity of sickle cell disease mandates ongoingfor patient historical education. Specific ReferenceUnderstanding Only the pathophysiology, treat- medical treatment modalities such as those ment, and complications of sickle cell dis- outlined in this management guide will ease is important so that health caregivers require the development of appropriate can provide optimal care. MLPs should be interventions individualized to maximize a resource for house staff members, inpa- compliance. During the initial assessment, tient and outpatient nursing staff members, the patient’s and/or family’s understanding and public health, school health, and other of the disease should be explored as well health staff members. Management confer- as their understanding of general and spe- ences and workshops are effective methods cific treatment plans. It is important that of education. A comprehensive health care the family thoroughly understands both the team, including physicians, social workers, general and specific treatment plans before genetic counselors, and MLPs, offers the they are implemented. The MLP must best approach to effective health care assess the patient’s and family’s knowledge delivery and education. base of sickle cell disease regularly. HOME HEALTH CARE TRANSITION FROM PEDIATRIC TO MANAGEMENT OF PAINFUL ADULT CARE EPISODES Many factors must be considered before Painful episodes are the most common the transition from pediatric to adult health complication of sickle cell disease. Home care can occur. The process can be trau- health care management and close tele- matic for medical staff members and the phone followup can reduce the need for family as well as the patient. The patient frequent hospital visits. Because fever can must be ready developmentally and must be a sign of infection or extensive tissue have the full support of the family as well damage, patients should be urged to pur- as the pediatric and adult staff members. chase thermometers and learn how to use As patients leave the pediatric setting, they them prior to telephone contacts. The will have to learn how to assume increas- health care practitioner can provide infor- ing responsibility for their own health care. mation about home comfort measures such This move toward independence will be as warm baths or showers, massages, and reflected in other aspects of their life such relaxation therapy. Pain that requires med- as in their job, school, and relationships. ical evaluation rather than home care Ideally, patients should attend joint pedi- should be carefully reviewed with the atric/adult sessions and then move gradual- patient (see Chapter 7, Painful Events). ly to full adult care. Participation in a support group may help the patient LEG ULCER CARE through the transition. Efforts must be Evaluation of the patient’s understanding of made to transfer medical records and other the prescribed treatment plan (see Chapter

16, Leg Ulcers) should be done at each planning and referral to appropriate contact. Demonstration of how the treat- resources when indicated. ment plan will be administered at home should help toArchive increase compliance. Home OUTPATIENT CARE care referral should be made if indicated. In the outpatient setting, the MLP should Successful outpatient and home manage- focus on health maintenance, prevention, mentfor for chronic, historical recurring leg ulcers Reference Only early recognition, treatment of complica- reduces the need for hospitalization. tions, and patient education. Evaluations should identify patient and practitioner CHELATION THERAPY concerns about illness, analgesic therapy, A chronic transfusion program may be management, compliance, social adjust- instituted to treat severe complications of ment, and school and/or work perfor- sickle cell disease (see Chapter 10, mance. Health care plans are developed to Transfusion). Patients on chronic transfu- help patients maintain wellness and to be sion programs should be evaluated for iron active participants in receiving the best overload (hemosiderosis). When iron over- possible care. A close relationship with load is documented, chelation therapy with school health faculty is beneficial for deferoxamine mesylate (Desferal®) may be school-age patients. initiated. The MLP should develop a teach- ing plan for home chelation, and written EMERGENCY DEPARTMENT CARE instruction must be provided to assist the MLPs must identify and promptly treat patient or parent through each step of the acute events associated with sickle cell dis- procedure. Compliance with home chela- ease. Proper education of emergency room tion therapy must be monitored carefully. staff members will ensure a timely The MLP should coordinate yearly visits to response to life-threatening complications ophthalmology and audiology specialists (i.e., sepsis, acute anemic events). To help for early detection of possible adverse provide continuity of care, an updated effects of deferoxamine mesylate. database that includes baseline hematologic values and other pertinent information nec- INPATIENT CARE essary for providing emergency care should After a careful history and physical assess- be maintained. Communication is essential ment are done, a health care plan using between emergency department staff mem- techniques proven effective in the past can bers and the sickle cell clinic or physician’s be instituted and appropriate goals for hos- office. pitalization established. Continuity of care is important for the hospitalized patient. SUMMARY Thus, the assignment of a primary caregiv- Patient care interventions for individuals er can help to reduce the stress of the hos- with sickle cell disease are both supportive pitalization and associated fears. This indi- and treatment oriented. A delicate balance vidual should explain hospital procedures must exist between providing supportive and specific treatment modalities to the care and fostering independence to ensure patient carefully. Finally, the primary care- that patients become well-informed, active giver should also participate in discharge participants in their care.

BIBLIOGRAPHY Rivers R, Williamson N. Sickle cell anemia—complex disease, nursing challenge. Butler DJ, Beltran LR. Functions of an adult RN J 1990;53:24-9. sickle cell group: education,Archive task orienta- tion, and support. J Health Soc Work Rosen DS. Transition to adult health care 1993;18:1. for adolescents and young adults with cancer. Cancer 1993;71(suppl):3411-4. Cohen A,for Martin historicalM, Mizanin J, Konkle DF,Reference Only Schwartz E. Vision and hearing during Schidlow DV, Fiel B. Live beyond pedi- deferoxamine therapy. J Pediatr 1990;117(2, atrics. Transition of chronically ill adoles- Part 2):326-30. cents from pediatric to adult health care systems. Med Clin North Am 1990;74:1113-9. Pack B (guest ed). Symposium on sickle cell disease. Nurs Clin North Am March Vichinsky E, Johnson R, Lubin B, et al. 1983;18:129-229. Multidisciplinary approach to pain management in sickle cell disease. Am J Pediatr Hematol Oncol 1982;4:3.

CHAPTER 4 PSYCHOSOCIALArchiveMANAGEMENT for historical Reference Only

As in other chronic illnesses, psychosocial housing, medical, and financial assistance. issues affect social, emotional, academic, The social services department may also and vocational adaptation to sickle cell dis- provide case management services that link ease throughout the patient’s life cycle. The and coordinate counseling and support patient’s care providers must be aware of services for the family. these factors and respond appropriately. In addition to addressing the concrete Many of the psychosocial factors are asso- medical needs of the patient and family, ciated with developmental life stages. The attention must be given to their emotional following is a developmental framework and psychological needs. The physician for examining the psychosocial aspects should provide an opportunity for the par- of sickle cell disease. Suggestions for ents to talk, ask questions, and express appropriate interventions are offered. their feelings (anger, guilt, fear, denial, helplessness, etc.). These sessions should THE INFANCY THROUGH be repeated as necessary. Parents should PRESCHOOL STAGE be given factual information about their Early and appropriate psychosocial coun- child’s condition, its inheritance, and prob- seling for the family of a newly diagnosed lems that may occur in the future. Parents infant with sickle cell disease is extremely also need information and instruction on important. Parents may have a number of how best to provide home management concerns pertaining to social, emotional, and care of their infant. With sound teach- and environmental issues related to their ing, encouragement, and support, the par- baby’s diagnosis. Such issues may include ents can become effective participants with nutrition, health insurance, the need for health care professionals in the care of adequate housing, and assistance in deal- their child. This approach can have a posi- ing with feelings (“genetic guilt”) about tive influence on parental coping and having a child with a chronic hereditary compliance. illness. In some cases, counseling and reassurance To assist families with the multiple non- of parents by the physician is not sufficient medical issues that might confront them, to allay anxiety and reduce guilt or resolve health care providers need to know about deep-seated emotional and psychological available community resources. For exam- conflicts. Referral to a family and child ser- ple, the local social services department or vices agency or other community mental a State government’s Crippled Children’s health facility can be helpful in this situa- Program may be able to identify potential tion. With specialized individual, family,

and group counseling, parents together or them fully with the parents and others individually are usually able to work involved, and understand completely the through social, emotional, and environmen- nature of the request. Although these tal conflicts. Often, Archiveparental understanding requests relative to their child’s school may and comprehension of the genetic implica- be appropriate and valid, they may also be tions of their child’s medical condition indicative of the parents’ need for a better remain inadequate.for historical If so, ongoing associa- Referenceunderstanding Only of their child’s health status tion with genetic counseling services and his/her actual limitations. Children should be considered. should be encouraged to study and remain in school. Although school attendance may Established programs in the community be interrupted periodically due to illness that provide services to patients and fami- (usually infections and painful episodes), lies affected by sickle cell disease or other once the illness is resolved the child genetic disorders should be used. Parents should return to school and other usual can also benefit from interacting with other activities. Hospital-based school programs parents in mutual support and self-help can assist the child who has frequent hos- groups. pitalizations to maintain age-appropriate school performance. THE SCHOOL-AGE STAGE To accommodate the child’s school pro- Children with sickle cell disease should be gram, physician visits should be scheduled enrolled in a regular classroom unless there after school hours when possible. are specific reasons to do otherwise. Telephone followups are often helpful. Parents should notify appropriate school Socialization and peer interaction are officials of their child’s condition. It is help- important functions of the educational sys- ful to have written information that can be tem, and inappropriate use of a home shared with the teacher, school nurse, and tutoring program during and following ill- other school officials. This information can nesses can interfere with the child’s social be in the form of a brochure or pamphlet and psychological development. Usually containing general information about sickle this service is not needed unless the child cell disease or a letter from the patient’s is convalescing at home for more than 2 physician specifically describing the child’s weeks. During brief illnesses at home, par- condition and any special needs. Medical ents can request that the child’s teacher or nursing staff should be available to pro- assign a study partner to bring assignments vide consultation and education to teachers home to the patient and keep him or her about sickle cell disease. abreast of school activities. Because school Parents may ask the physician to complete policies vary, parents should check with a variety of forms or write letters describ- the school or school board to find out ing their child’s illness and its management what services or resources are available. or requesting special bus transportation, The physician and nurse practitioner can the use of special school facilities (such as be extremely important advocates. an elevator), exemption from certain physical education activities, or home or hospital Recognition of the importance of school school instruction. The physician should does not negate the importance of other consider these requests carefully, discuss activities of a growing child. Like all

children, children with sickle cell disease group counseling. Therapy groups that should be encouraged to have hobbies and include teenagers with the same or similar other age-appropriate interests. Parents disabilities can be very successful. A sup- should understandArchive that children with sickle port group for adolescent patients is espe- cell disease need not be treated any differ- cially important because they may hide ently from unaffected children. This is their disease from peers and teachers. Such especiallyfor truehistorical during the quiescent Reference periods groups helpOnly teenagers learn how peers when there are no sickle cell-related prob- cope with common problems and concerns. lems. Keeping the child’s lifestyle as nor- Overprotection by parents, family, and mal as possible helps in development of a friends can pose very serious problems for positive self-image. Many children with some adolescents. They want to be inde- sickle cell disease have successfully attend- pendent but are forced to be dependent ed summer camp, some camps specifically when they become ill. Sensitive counseling for children with sickle cell disease and of both parents and the adolescent can be others unrelated to sickle cell disease. Such helpful. The physician dealing with the activities foster independence and provide adolescent must keep the parents informed the child with an opportunity to be more and give them an opportunity to participate similar to his or her peers. in medical decisions. THE ADOLESCENT STAGE Delayed development of secondary sexual characteristics and/or slow physical growth Adolescence (ages 13 to 19) represents a in adolescent patients requires counseling period of transition marked by physical, and reassurance. Just like other teenagers, emotional, and social changes. There may teenage patients with sickle cell disease be concerns for adolescents with sickle cell want to resemble their unaffected peers disease in this age group. This is the stage in every way, including capabilities and when concerns about body image, peer interests. group acceptance, and physical attractive- ness are very important. Specific physical Often the physician is asked by the adoles- characteristics and complications of sickle cent with sickle cell disease if he or she cell disease can hinder the social and emo- can participate in sports or other activities tional adjustment of the affected teenager. that require considerable physical strength Such characteristics as jaundiced eyes, and endurance. In the absence of con- enuresis, delayed physical maturation and traindications, participation in such activi- growth retardation, unpredictable pain ties should be encouraged. The teenager episodes, and complications such as avas- with sickle cell disease needs to be able to cular necrosis of the hip joint, chronic leg set his or her own pace when participating ulcers, and the residual effects from stroke in activities such as swimming, tennis, or can make coping very difficult. Episodes of basketball and should be able to stop and priapism require both medical and psycho- rest when tired. Some teenagers may be logical care, especially in adolescents. able to compete in competitive sports. Fortunately, only a few teenage sickle cell patients are faced with these complications, Sexuality in the teenager with sickle cell and they may benefit from individual or disease is often no different from that in

their more healthy peers. Some will be sex- this employment is unstable and does not ually active, and it is important to provide offer fringe benefits like health insurance advice on contraception and sexually trans- coverage. Assistance with payment for mitted diseases. FailureArchive to acknowledge medical services may be available for adult problems of sexuality and associated risks sickle cell patients through the local public may result in serious complications later. medical assistance program, Social Security When appropriate,for historical adolescents should Referencebe Administration, Only and State vocational reha- referred to family life clinics. Pregnancy in bilitation services. adolescents with sickle cell disease pre- Most sickle cell patients do not show obvi- sents medical, psychological, and social ous disability, and it may be difficult for problems. Pregnant adolescents can usually them to qualify for assistance. Eligibility for benefit from counseling and services public assistance in disability and offered by a social worker. Supplemental Security Income programs is At this stage of life, teenagers should give based on the extent of the disability as well serious consideration to college, careers, as income eligibility. The patient must and their future as adults. Discussion with qualify in both categories to be determined gainfully employed adults with sickle cell eligible. The physician’s report of the disease, particularly with professionals who patient’s physical status is crucial in helping have sickle cell disease, can be very help- to determine his or her eligibility. The ful. Adolescent sickle cell patients should physician should carefully document the be encouraged to consider careers that are clinical course of the patient’s illness, consistent with their medical condition. including the number and dates of hospital Such career aspirations often require col- admissions, emergency room visits, acute lege or vocational training. Referral to visits, organic and physical dysfunctions, vocational rehabilitation, precollege orien- and the blood count and the need for tation programs, or other training and blood transfusions. To provide a com- career programs can be extremely helpful. prehensive picture of the patient’s condi- Referral to key community resource agen- tion, it may be necessary to provide more cies such as departments of employment information than that specifically requested. (job services) and social or youth services In addition to social and environmental dif- can establish important linkages. ficulties, the adult patient may experience emotional and psychological problems, THE ADULT STAGE including relationship difficulties, loneli- Adult patients with sickle cell disease may ness, low self-esteem, and preoccupation encounter psychosocial and socioeconomic with death. Consultation with or referral to problems, including unpredictable interrup- a mental health practitioner is beneficial to tions of social and economic life due to the patient and physician when he or she recurring painful episodes. Adults are often observes patient behavior that is indicative faced with unemployment, lack of health of failure to cope, depression, or other insurance coverage, and inability to qualify signs of psychological or emotional dys- for public assistance or disability insurance. function. Support and self-help groups may If the young adult is employed, frequently be beneficial for these patients.

BIBLIOGRAPHY Hurtig AL, Viera CT. Sickle cell disease: psychological and psychosocial issues. Urbana Conyard S, Krishamurthy M, Dosik H. and Chicago: University of Chicago Press, Psychosocial aspects of sickle cell anemia Archive1986. in adolescents. Health Soc Work 1980;5:20- 6. Kumar S, Powars D, Allen J, Haywood LJ. Anxiety, self concept, and personal and Duncanfor D, historicalScott RB. Coping with Referencesickle Only social adjustments in children with sickle cell disease: a profile and perspective of a cell anemia. J Pediatr 1976:88(5):859-63. pioneer self help group. J Natl Med Assoc 1988;80:221-4. Leavell SR, Forg CV. Psychopathology in patients with sickle cell disease. Eisenberg MG, Sutkin LC, Mary AJ (eds). Psychosomatics 1983;24:23-5, 28-9. Chronic illness and disability through the life span. Effects on self and family. New Nash KB (ed). Psychosocial aspects of sickle York: Springer Publishing Company, 1984. cell disease: past, present, and future direc- tions of research. New York: Haworth Gilbert SK. The health insurance plight of Press, Inc., 1994. patients with sickle cell disease. J Natl Med Assoc 1986;78:663-5. Newman B, Newman D. Development through life. Illinois: Dorsey Press, Hobbs N, Perrin JM. Chronically ill children 1978:187-211. in America. Rehabil Lit 1984;45:7-8. Weiss JO. Psychosocial stress in genetic dis- Hobbs N, Perrin JM, Henry TD. Chronically orders: a guide for social workers. Soc ill children and their families. San Work Health Care 1981;6:17-31. Francisco: Josey-Bass Publishers, 1985.

Archive for historical Reference Only

CHAPTER 5 NEWBORNArchiveSCREENING for historical Reference Only

Newborn screening for sickle cell disease is All infants, of every ethnic group, should an effective first step to reduce morbidity be tested to ensure the identification of all and mortality in individuals with the dis- affected newborns. Where possible, sickle ease. Parents of newborns with a positive cell disease screening should be coupled screening test result for sickle cell disease with other newborn screening tests per- must be contacted before the child formed to detect hypothyroidism and becomes 2 months of age to confirm the inborn errors of metabolism. Several diagnosis. The diagnosis should be con- screening methodologies are acceptable, firmed by a laboratory with expertise in including hemoglobin electrophoresis on analysis of variant hemoglobins. If a child cellulose acetate and citrate agar, isoelectric who is presumed to have sickle cell dis- focusing, and high-pressure liquid chro- ease through newborn screening is not matography. Because of the high concen- retested by 4 months of age, he or she tration of Hb F in newborns, solubility tests should be started on penicillin VK (125 mg or sickle cell preparations (sodium given orally twice a day) pending confir- metabisulfite) should not be used to con- mation; the medication can be discontin- firm the presence of Hb S until the infant ued in the rare instance that the hemoglo- has reached 12 months of age and should bin screening test result was erroneous or never be used as a sole diagnostic labora- is found to represent a benign disorder. tory procedure. States that test for sickle Once the disease diagnosis is confirmed, cell disorders as part of their newborn the infant must receive care in an ongoing screening procedures usually confirm the and comprehensive medical program that original test result by retesting the child includes oral penicillin given twice a day and will also request a repeat specimen if for the prevention of overwhelming the history indicates that the child was transfused before the blood sample was Streptococcus pneumoniae infection and obtained. It must be emphasized that the parent education about sickle cell disease. responsibility for a final and definitive The medical program should be staffed by diagnosis rests with the child’s physician. health care professionals who are sensitive to the special needs of infants with sickle Red cells of normal newborns contain cell syndromes and are aware of their hemoglobins F and A, “FA,” the hemoglo- propensity to life-threatening infection and bin in highest concentration being listed death from complications such as acute first. The hemoglobin pattern or phenotype splenic sequestration and acute chest is due to predominance of Hb F at birth. syndrome. Newborns with sickle cell trait have an

“FAS” phenotype, with more Hb A than Hb and the variant, further diagnostic tests are S. Infants with SC disease have an “FSC” usually unnecessary, if the child is hemato- pattern, those with SS disease, Sβo thal, logically normal in other aspects. and S HPFH each haveArchive an “FS” phenotype on newborn screening. Although infants BIBLIOGRAPHY with Sβ+ forthal will historical generally have an “FSA” ReferenceGrover R, Shahidi Only S, Fisher B, et al. Current pattern on screening, the percentage of Hb sickle cell screening programs for new- A may be so small that these infants will borns in New York City, 1979-80. Am J also have an “FS” phenotype. Definitive Public Health 1983;73:249-52. diagnosis may require testing both parents or deoxyribonucleic acid (DNA) typing of Newborn screening for sickle cell disease the infant or retesting the infant after 9 and other hemoglobinopathies. Pediatrics months. It is important to remember that (suppl) 1989;83(5). newborns with “FA” patterns are not neces- Pearson HA, O’Brien RT, McIntosh S, et al. sarily hematologically normal—they do not Routine screening of umbilical cord blood have sickle cell disease but may have tha- for sickle cell disease. JAMA lassemia or another disorder of red blood 1974;227(4):420-1. cells. When definitive diagnostic tests cannot be performed in early infancy, it is best Powars DR. Natural history of sickle cell to assume that the infant has SS disease, disease: the first ten years. Semin Hematol the most common of the FS disorders. 1975;12(3):267-85. When infants are doubly heterozygous for Rogers DW, Clarke JM, Cupidore L, et al. sickle cell and another abnormal hemoglo- Early deaths in Jamaican children with sick- bin other than C, definitive identification by le cell disease. Br Med J 1978;1(6126):1515- a knowledgeable hematologist is necessary. 6. In addition to identifying the affected new- Stern KS, Davis JG (eds). Newborn screen- born, newborn screening also provides an ing for sickle cell disease: issues and impli- opportunity to identify couples at risk for cations. New York: Council of Regional having children with sickle cell disorders. Networks for Genetic Services, Cornell Parents of newborns identified with sickle University Medical College, 1984. (Copies cell trait or hemoglobin C trait should be available from the National Maternal and offered testing for all hemoglobinopathies, Child Health Clearinghouse). including thalassemia, and be appropriately US Department of Health and Human counseled. Services, Public Health Service, Sickle Cell Newborn screening may identify variant Disease Guideline Panel. Sickle cell dis- hemoglobins other than S or C. When ease: screening, diagnosis, management, these are co-inherited with Hb S, a defini- and counseling in newborns and infants. tive diagnosis must be made. Hemoglobin Clinical Practice Guideline Number 6. o S Arab disease, for instance, is as serious a Rockville, Maryland: Agency for Health condition as SS disease, while the combina- Care Policy and Research, 1993; AHCPR tion of Hb S and Baltimore is as benign as publication no. 93-0562. sickle cell trait. If the child has only Hb A

CHAPTER 6 INFECTIONArchive for historical Reference Only

Serious bacterial infections are a major Antibiotic Prophylaxis cause of morbidity and mortality in patients Prophylactic penicillin is so effective in with sickle cell disease. Severe, overwhelm- reducing the number of life-threatening ing septicemia/meningitis due to S. pneu- episodes of pneumococcal sepsis in chil- moniae is the most common cause of dren with SS disease under age 5 years that death during early childhood, but enteric most States screen newborns for the dis- organisms emerge as important pathogens ease so they can be placed on the drug by in older patients. Because of the patient’s 2 to 3 months of age. Oral penicillin VK asplenic condition, and because of disor- dered humoral immunity, infections in (125 mg given twice a day up to age 3 patients with SS disease are more likely to years, then 250 mg given twice a day) is cause morbidity, disseminate, and resist the preferred form of treatment. eradication than in individuals unaffected Prophylaxis should be given to children βo by the disease. Infections also may with SS disease and S thal starting at 2 to enhance susceptibility toward vaso-occlu- 3 months of age and continuing until at sive complications. Prevention and early, least age 5 years. Prophylaxis in older chil- aggressive treatment of infection are critical dren has not been shown to be beneficial in the management of patients with sickle and may be unnecessary after pneumococ- cell disease. cal immunizations are complete and antibody titers are protective. Some clinicians PREVENTION give prophylaxis to children with SC disease or Sβ+ thal: there is an increased risk Immunization of severe infection in such patients, although it is less than in SS disease or Sβo Children with SS disease have a normal thal. Compliance with penicillin prophylax- antibody response to vaccines and should is can be achieved, provided that a dedicat- receive all immunizations recommended by ed team of physicians, nurses, and health the American Academy of Pediatrics (these care educators engage families in intensive change periodically, and the most current educational programs. recommendations should be followed (see Table 2)). In addition, children should Neither the pneumococcal vaccine nor receive pneumococcal vaccine. Some clini- available antibiotics has been shown to cians recommend that the influenza vaccine eliminate nasopharyngeal colonization with be administered according to epidemiologic S. pneumoniae, Neisseria meningitis, and considerations. H. influenzae in normal young children or

Table 2 Recommended ImmunizationsArchive Birth (or at first visit) Hepatitis B vaccine #1, hepatitis B immunoglobulin if mother HBsAg† 1 formonth old historical (or 4 weeks after first visit) Reference Hepatitis B vaccine #2 Only 2 months old DTaP #1, HbcV #1* or Tetrammune, OPV #1 4 months old DTaP #2, HbcV #2 or Tetrammune, OPV #2 6 months old DTaP #3, HbcV #3, OPV #3 or Tetrammune, hepatitis B vaccine #3 (or 6 months after second vaccine) 12 to 15 months old Measles, mumps, rubella (MMR) 5 months old HbcV booster 15 to 18 months old DTaP booster #1, OPV #3 24 months old Pneumococcal vaccine 4 to 6 years old DTaP booster #2, pneumococcal vaccine booster, OPV #4, MMR (at or before school entry) 14 to 16 years old TD booster Annually Influenza vaccine

*See MMWR 1993;42:RR-13, (combination of DPT and HbcV) can be used to replace these vaccines. †See Pediatrics 1994;94:774-5; AAP Committee on infectious disease regarding polio vaccine at 6 months. DTaP = diphtheria tetanus acellular pertussis vaccine. DTP = diphtheria tetanus pertussis vaccine. HbcV = Haemophilus influenzae type b conjugate vaccine. OPV = oral polio virus vaccine. TD = tetanus diphtheria toxoids vaccine. those with sickle cell disease. Prophylactic may well undergo tremendous change dur- antibiotics prevent bacteremia and tissue ing the next few years. At present, the invasion, despite continued nasopharyngeal most effective approach is a combination carriage or reexposure. When failure of traditional pneumococcal vaccination occurs, it may be due to a variety of micro- and regular penicillin prophylaxis; it is biologic causes as well as a lack of patient hoped that newer conjugated pneumococcal compliance. As discussed below, the emer- vaccines will prove protective in infancy. gence of penicillin- and cephalosporin- resistant S. pneumoniae is a serious evolv- MANAGEMENT ing problem in many communities and may ultimately undermine the effectiveness Pediatric Infection of the established prophylactic regimen. Clinicians should be aware that recommen- Fever in a child younger than age 5 years dations concerning the use of prophylactic with SS disease often indicates life-threaten- penicillin and the choice of empiric antibi- ing bacterial infection. It is estimated that otics in patients with sickle cell disease there is a 400-fold increased risk of pneu-

mococcal septicemia/meningitis in this ■ Seriously ill appearance. population. Fortunately, H. influenzae ■ Hypotension. infections have become exceedingly rare with the adventArchive of the H. influenzae ■ Poor perfusion, dehydration. vaccine. ■ Pulmonary infiltrate. Children with sickle cell disease and sep- for historical Reference■ Corrected Only white blood count greater than ticemia generally have fever greater than 30,000 or less than 5,000/mm3. 102 oF (38.9 oC), but temperatures below 3 102 oF may also be seen, especially early ■ Platelet count less than 100,000/mm . in the clinical course. In febrile children ■ Hemoglobin less than 5 g/dL. with sickle cell disease, administration of ■ History of S. pneumoniae sepsis. antibiotics should occur promptly, even for minimal clinical indications such as signifi- Several centers with expertise in treating cant fever, chills, etc. The patient should be large numbers of patients with sickle cell evaluated for causes of fever such as otitis disease in an ambulatory setting have suc- media, pneumonia, or urinary tract infec- cessfully used long-acting parenteral tion. Chest x-ray, blood, urine, and throat cephalosporins (e.g., ceftriaxone sodium) cultures should be obtained without wait- to treat febrile children as outpatients. This ing for test results. Lumbar puncture should approach is appropriate only when the be performed even if there are only mini- following conditions apply: mal indications of meningitis. An antibiotic ■ The patient is clinically at low risk for effective against S. pneumoniae and H. sepsis (i.e., none of the above factors is influenzae should be promptly adminis- present). tered, preferably intravenously. Because ■ The patient, family, and clinic are capa- penicillin- and cephalosporin-resistant S. ble of impeccable followup, and the pneumoniae are now identified in many patient has immediate emergency access regions of the country, antibiotics such as to the hospital. vancomycin have been added to the typical empiric therapy regimen in those areas. It ■ The endemic flora have been demon- is critical to be aware of the susceptibility strated to be sensitive to cephalosporins. patterns of the local flora when selecting ■ A successful followup program has been empiric therapy. The choice of subsequent established. antibiotics can be guided by results of If septicemia is confirmed by a positive cultures and clinical course. blood culture, the child should be hospital- Practice varies widely on indications for ized, and therapy should be continued for admitting febrile SS children to the hospi- a minimum of 5 to 7 days. Bacterial menin- tal. There is, however, consensus that all gitis should be treated for 10 days or at SS children with any of the following be least 7 days after cerebrospinal fluid steril- admitted for inpatient treatment: ization has occurred. On the other hand, if blood, urine, and throat cultures are nega- ■ Temperature greater than 40 oC (> 104 oF). tive after 3 days and the patient is well, antibiotic therapy can be discontinued and

the diagnosis presumed to be a viral ill- fluid) before long-term antibiotics are start- ness. If fever persists and cultures are ed to treat osteomyelitis or septic arthritis. negative, the patient should be reevaluated. Blood cultures may be particularly helpful Archivein the setting where infarcted bone is seeded Infections in Older Children and during an episode of bacteremia. Adults for historical ReferenceIncreasing antibiotic Only resistance among Because pneumococcal infections become Salmonella isolates is a major problem. less frequent after the first decade of life Even if in vitro susceptibility tests suggest and infections due to other pathogens efficacy for tetracyclines, cephalosporins, found in the general population become and aminoglycosides, these antibiotics more common, a systematic bacteriologic often fail. Ampicillin, quinolines, and evaluation should be used before adminis- trimethoprim-sulfamethoxazole have been tering antibiotics. A persistent fever higher demonstrated to be effective (when indicat- than 101 oF should not be assumed to be ed by in vitro sensitivity tests). Chlor- due to vaso-occlusive crisis. Infections tend amphenicol can also be effective, but its to occur in already damaged areas such as potential for bone marrow suppression lungs, kidneys, and bones. requires frequent monitoring of the reticulocyte count. The tendency of Salmonella Urinary Tract Infections to establish chronic, intracellular infection requires prolonged treatment—typically 1 Pyelonephritis in patients with SS disease is month of intravenous antibiotic therapy, difficult to treat, recurs regularly, and is followed by months of oral treatment. often associated with septicemia. This is Public health procedures should be imple- particularly serious during pregnancy. mented to prevent spread of infection to Urine cultures are essential before therapy family members. and should be repeated 1 to 2 weeks after cessation of therapy. Treatment consists of Bacteriologically proven staphylococcal antibiotics and hydration. Urologic evalua- osteomyelitis requires high-dose penicilli- tion and chronic suppressive antibiotic nase-resistant penicillin (e.g., nafcillin) for therapy may be appropriate for patients several weeks. If adequate blood levels of with repetitive infection. the antibiotic can be achieved, a regimen such as 2 weeks of intravenous therapy followed by 4 to 6 weeks of oral therapy can Osteomyelitis be given. The necessity for surgical incision Osteomyelitis must be differentiated from and drainage or débridement in osteo- the more common (~50:1) diaphyseal bone myelitis of any cause should be based on infarction because the two conditions pre- clinical judgment. sent with similar clinical and imaging findings but are treated differently. Similarly, BIBLIOGRAPHY septic arthritis must be distinguished from Breiman RF, Butler JC, Tenover FC, Elliott the more common joint effusion associated JA, Facklam RR. Emergence of drug-resis- with acute painful episodes. It is essential tant pneumococcal infection in the United to establish a bacterial diagnosis (from States. JAMA 1994;271:1831-5. blood or aspirated joint or subperiosteal

Gaston MH, Verter JI, Woods G, et al. type 6B and Haemophilus influenzae type Prophylaxis with oral penicillin in children b capsular polysaccharide-tetanus toxoid with sickle cell anemia. N Engl J Med conjugates in two- to five-year-old children 1986;314:1593.Archivewith sickle cell anemia. Pediatr Infect Dis 1990;9:181-6 (erratum, Pediatr Infect Dis Leggiadro RJ. Penicillin- and cephalosporin- 1990;9:308). resistantforStreptococcus historical pneumoniae Referenceand Only emerging microbial threat. Pediatrics Shapiro ED, Berg AT, Austrian R, et al. The 1994;93:500-3. protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Overturf GD, Powars D, Baraff LJ. Bacterial Med 1991;325:1453-60. meningitis and septicemia in sickle cell disease. Am J Dis Child 1977;131:784-7. Wilimas JA, Flynn PM, Harris S, et al. A randomized study of outpatient treatment Pearson HA, Gallagher D, Chilcote R, et al. with ceftriaxone for selected febrile chil- Developmental pattern of splenic dysfunc- dren with sickle cell disease. N Engl J Med tion in sickle cell disorders. Pediatrics 1993;329:472-6. 1985;76:392-7. Zarkowsky HS, Gallagher D, Gill FM, et al. Sarnaik S, Kaplan J, Schiffman G, et al. Bacteremia in sickle hemoglobinopathies. J Studies on pneumococcal vaccine alone or Pediatr 1986;109:579-85. mixed with DTP and on pneumococcus

CHAPTER 7 PAINFUL EArchiveVENTS for historical Reference Only

Painful crises in sickle cell disease are and a baseline white blood cell (WBC) believed to be caused by ischemic tissue count of 15,000 are factors that place indi- injury resulting from the obstruction of viduals at greatest risk. A painful crises is blood flow produced by sickled erythro- one of the most common settings in which cytes. The reduced blood flow causes death occurs in adult patients. Acute chest regional hypoxia and acidosis, which fur- syndrome, central nervous system events, ther increases the sickling process and may bone marrow embolism, and acute multi- increase the ischemic injury. Painful crises organ failure syndrome may suddenly vary in intensity and duration, usually last- occur during a severe painful crises. In a ing 4 to 6 days but sometimes persisting patient in pain, overtreatment with narcotic for weeks. They may vary in intensity from drugs or intravenous fluids and other iatro- time to time during the course of a single genic events increase the morbidity of ther- episode. Hypoxia, infection, fever, acidosis, apy. Pain management requires ongoing dehydration, menstruation, sleep apnea, assessment of the patient for sites of pain, obstructive snoring, and exposure to cold degree of pain, and effects of pain and may precipitate such events. In addition, pain relief on at least a daily basis. patients often cite anxiety, depression, and Pain should be treated as early as possible physical exhaustion as precipitators. In because undertreatment or persistent pain many instances, no precipitating event can can debilitate the patient both physically be identified. and psychologically. Some of the recog- The frequency and severity of repeated nized physical sequelae of unrelieved pain painful crises vary widely among patients. such as stress and dehydration are also A few patients state that they are always precipitating events for acute painful “in pain” and repeatedly request hospital- episodes and may account for the not ization. Conversely, approximately one- uncommon finding of a patient who initial- third of patients rarely seek hospital-based ly presents with focal pain but develops treatment. Many patients can manage diffuse pain within hours of the onset of painful events at home. the crises. In general, painful crises are a measure of disease severity and have been reported to ASSESSMENT OF PATIENTS correlate with early death in adult patients, There is no clinical or laboratory finding but we are unable to predict which individ- that is pathognomonic of painful episodes uals will be so adversely affected. High in sickle cell disease. The diagnosis of a hemoglobin levels, low fetal hemoglobin, painful episode is often made solely on the

basis of the medical history and physical ■ Acute pulmonary symptoms. examination. The possibility that pain is ■ Neurologic symptoms or pain associated precipitated by a concurrent medical condi- with extremity weakness or loss of tion such as infectionArchive should be consid- function. ered, and the physician should search for a precipitatingfor illness historical in every instance. Reference■ Acute joint Onlyswelling. Bones are the most common site of pain. ■ Recurrent vomiting. Dactylitis, or the hand-foot syndrome ■ Pain not relieved by conservative (acute, painful swelling of the hands and measures. feet), is the first manifestation of sickle cell disease in many infants. Irritability and ■ Priapism. refusal to walk are other common symptoms. After infancy, musculoskeletal pain LABORATORY TESTS can be symmetrical, asymmetrical, or ■ Painful events are not commonly associ- migratory, and it may or may not be asso- ated with changes in the patient’s usual ciated with swelling, low-grade fever, red- hemoglobin level. Concurrent reticulocy- ness, or warmth. In both children and topenia is occasionally present. The adults, sickle vaso-occlusive episodes are WBC may be similar to the patient’s difficult to distinguish from osteomyelitis, baseline value; a higher value with an septic arthritis, synovitis, rheumatic fever, elevated band count suggests that infec- or even gout. tion is present.

When abdominal or visceral pain is pres- ■ If a fever greater than 101 oF is present, ent, care should be taken to exclude an aggressive evaluation should be done sequestration syndromes (spleen, liver) or to find the source (see Chapter 6, the possibility of an acute condition such Infection). as appendicitis, pancreatitis, cholecystitis, ■ If pulmonary symptoms are present, a urinary tract infection, pelvic inflammatory chest x-ray should be obtained, and disease, or malignancy. Pneumonia (“chest measurement of arterial blood gases syndrome,” see Chapter 8) develops during should be considered (see Chapter 8, the course of 20 percent of painful events Lung). and can present as abdominal pain. In adults, chest pain may be due to vaso- ■ If osteomyelitis or septic arthritis is sus- occlusion in ribs and often precedes a pul- pected, direct aspiration of the bone or monary event. The lower back is also a site joint and cultures of the aspirates should for painful crises in adults. be obtained. Radiographs and radioiso- tope or MRI scans may help separate Patients should be seen by a physician infarction from infection, but they are immediately if any of the following high- not always reliable. risk factors exist: ■ Serum electrolytes and blood pH levels ■ Fever greater than 101 oF, lethargy, dehy- should be obtained for severely ill dration, or pallor. patients. There is a relatively high inci- ■ Severe abdominal pain. dence of electrolyte disorders in patients

with sickle cell disease, and a decreased in sickle cell disease so that patients can be weight may be an important sign of treated in the absence of individualized dehydration.Archivedata. GENERAL PRINCIPLES OF THERAPY Identification and Treatment of Any In general,for historicalthe management of acute ReferencePrecipitating Only or Associated Events painful episodes has five essential ele- The patient must be thoroughly evaluated ments, including health care provider- with an accurate history, physical examina- patient relationships, identification and tion, and assessment at each presentation treatment of any precipitating or associated for a painful crisis to be certain that no events, pain assessment, hydration, and other illness requiring specific treatment is analgesics. present. It is essential that a painful episode be considered a manifestation of Health Care Provider-Patient an underlying illness other than sickle cell Relationships disease until proved otherwise. These Patients with sickle cell disease have underlying illnesses are often infections or inflammatory conditions that require repeated episodes of sudden unexpected additional testing. pain that often result in fear of a life- threatening event or fear of how they will be treated by health care providers. The Pain Assessment health care provider should work to allevi- A comprehensive approach to pain assess- ate that fear by providing consistent empa- ment requires an evaluation of the patient’s thetic treatment. Ideally, continuity of care perception of pain, physiological respons- should be provided. If the patient must be es, and behavioral responses. However, the seen by someone unfamiliar with his or her mainstay of pain assessment must be clinical course and previous painful patient self-reporting. Neither behavior nor episodes, the new physician should discuss physiological responses replace the the patient’s care with a health care patient’s self-report. Patients in severe pain provider who is familiar with the patient. may use smiling, laughter, and singing as Because this may not always be possible, a coping mechanisms, and such actions consistent approach to pain discussed in should not be misunderstood. The goal of advance with the family and outlined in therapy is pain relief, and when it is the patient’s record is essential. Making a achieved, the patient may temporarily card available to the family and health care exhibit normal behavior (walking about, providers that describes the patient’s visiting). Such behavior does not necessari- steady-state laboratory test results (Hb, ly indicate that the episode is completely reticulocyte count, alloantibodies, biliru- resolved. bin), clinical problems, and pain medica- Each patient should be evaluated by a tion treatment can decrease certain prob- measurement tool that includes pain inten- lems and foster patient trust. In addition, sity and distress scales and an anatomic health care facilities should develop a gen- pain distribution assessment chart. The eral protocol for the management of pain course of the painful episode should be

accurately assessed using these tools at reg- excessive renal sodium losses occur in ular intervals (every 3 to 4 hours), particu- some patients, serum electrolytes should be larly before changes in medication are monitored at least every other day. In gen- made. Because patientsArchive often manage pain eral, serum sodium concentrations between at home and do not report pain to their 130 and 135 mg/dL do not need correction. physician, home pain diaries are helpful in Elevated sodium concentrations should be understandingfor and historical managing such pain. Referenceavoided. Physical Only examinations, including daily weight and records of intake and out- Hydration put, are essential. The presence of cardiomegaly on physical examination or chest Dehydration, which causes red cell dehy- x-ray usually does not indicate cardiac fail- dration and promotes sickling, frequently ure, and brisk parenteral rehydration usual- occurs in patients with sickle cell disease ly can be safely accomplished. Patients because of reduced fluid intake, increased should be monitored closely, however, for insensible water loss, and a high incidence tachycardia, tachypnea, rales, gallop of hyposthenuria. Because of hypos- rhythm, hepatomegaly, or excessive weight thenuria, measurement of urine-specific gain. gravity cannot be relied on to reflect the patient’s hydration status. For mild pain, Analgesics liberal oral hydration is sufficient. For patients with more severe pain, oral hydra- The goal of analgesic therapy is to provide tion should always be attempted if there prompt pain relief. Often, this is not are sufficient personnel to evaluate and achieved because of inadequate under- encourage fluid intake. Intravenous hydra- standing of the clinical pharmacology of tion is recommended in all other situations. analgesics, excessive concern about narcot- The basic objectives of fluid therapy ic addiction, or well-meaning but misguid- include correction of fluid and electrolyte ed use of placebos. There is no role for the deficits, maintenance of normal serum elec- use of placebos in the evaluation or treat- trolyte concentrations, and administration ment of the pain of sickle cell disease. The of fluid volumes (IV + P.O.) to equal 1-1/2 choice of therapy is based on potency, times the daily requirement. The choice of mode of action, and side effects of anal- initial parenteral fluid is dictated by the gesics (see Table 3). Medication should be patient’s hydration status and electrolyte administered on a fixed-time schedule, values. For uncomplicated painful crises, 5 with a dosing interval that does not extend percent glucose in 0.25-0.5 percent normal beyond the duration of the desired phar- saline is recommended as the initial fluid macological effect. Meperidine is con- replacement. The amount for adult patients traindicated in patients with renal dysfunc- is approximately 3 L/day if cardiac status is tion or central nervous system disease, normal, while that for children is based on because its metabolite normeperidine the patient’s weight. (which is excreted by the kidney) can cause seizures. Parenteral hydration should be monitored closely to avoid iatrogenic congestive heart Patient-controlled programs for severe pain, failure or electrolyte imbalance. Because either dose titration methods or patient-

controlled analgesia (PCA) devices, are the 8 mg of morphine every 3 hours, with preferred treatment methods. This 2-4 mg for pain occurring in the inter- approach maintains pain control, decreases val). Readjust fixed dosing if the anxiety, and addressesArchive individual pain patient requires more than three relief needs within an acceptable level of rescue doses in 12 hours. adversefor effects. historical Reference(3) After Only the loading dose, increase or Dose titration without PCAs may be done decrease the next fixed dose by one- using a number of techniques. It is essen- quarter to one-half, depending on the tial in any titration program that fre- patient’s response. quent, accurate, and timely assessment A PCA program usually includes an initial of the patient’s condition by a physi- loading dose when a narcotic has not been cian and nurse be done. If this is not given recently. The PCA pump delivers possible in the institution, considera- intravenous boluses of narcotic on patient tion should be given to transferring the demand at a preprogrammed dose and patient to an institution that can pro- interval. In addition, a lockout may be provide them. In all cases, a written plan grammed to prevent further dosing once a must be developed and implemented at the maximum dose in a 4-hour period has beginning of therapy; the results of the been reached. Because the patient adjusts assessment must be recorded, preferably his/her own dose, treatment is “titrated to on a flowsheet. Use the simplest dosing effect.” A continuous infusion setting is schedule and least invasive pain relief available and is often used for low-dose method first. The following are three regi- infusions, particularly at night. A typical mens that can be used. In each titration starting PCA program with morphine sulfate method, the first (loading) dose is based could be as outlined below: on prior analgesic history and the patient’s condition, including intensity and sites of 1. Loading dose (if needed) 0.05 mg pain: morphine/kg. (1) After the loading dose, reassess the 2. 1-hour dose limit 0.06-0.1 mg/kg/hr patient at 30-minute intervals and, (divided into 4-8 doses). based on the assessment, treat with 3. 4-hour lockout limit: 0.2-0.3 mg/kg. one-quarter to one-half of the loading dose until the patient experiences 4. A continuous night (10:00 pm-7:00 relief. This method requires very am) IV infusion rate of 0.02 mg/kg/hr close observation of the patient is added without changing the 4-hour and should not be used if this lockout limit. Other schemas such as cannot be provided. using a formula based on the previous 24 hours of care or treatment can be (2) Dose and dosing intervals are pre- found in the literature. scribed based on the patient’s prior history. “Rescue” dosing (for break- 5. Standard orders should include: through pain) is given at one-quarter a. No other narcotics given. to one-half the loading dose for recur- b. Close proximity to nursing rent pain between regular doses (e.g., station.

c. Patient training in PCA. drugs (NSAIDs) are a helpful adjunct in severe pain in patients who can tolerate d. Observations (which must be their gastrointestinal side effects because charted): Archivewhile they decrease inflammation at the tis- - respiratory rate q 1 hr sue site, they do not cause sedation, respi- - blood pressure, heart rate q 2 hr ratory depression, or bowel or bladder dys- for historical Referencefunction. They Only should not be used in chil- - pain and sedation scores q 2 hr dren or for more than 5 days because of - incentive spirometry q 1-2 hr the risk of gastrointestinal bleeding and when awake. renal disease. Ketorolac tromethamine, an NSAID, is available for parenteral use; pre- Records of the amount of analgesic actually liminary results suggest that it is helpful as administered and its clinical effect must be an adjunct or primary agent in moderate- carefully preserved, to help in managing to-severe pain. Oral NSAIDs may be useful future painful crises. in patients with chronic pain or arthritis. The effect of the route of administration on Care must be taken in patients with com- drug absorption must always be consid- promised renal function because these ered. The oral route is generally at least drugs may cause additional kidney dam- one-half (range one-half to one-sixth) as age. Aspirin, which can cause hyper- effective as the parenteral route, depending uricemia, should be avoided in patients upon the drug (see equi-analgesic table). with gout. Acetaminophen is the analgesic Oral administration, however, avoids many of choice if the patient is unable to tolerate of the complications of parenteral therapy. NSAIDs or aspirin. However, aceta- When potent narcotics are used, the physi- minophen should be used with caution in cian should remember that side effects patients with liver disease because it can include respiratory depression, nausea, cause severe hepatic damage in high vomiting, pruritus, hypotension, constipa- doses. Like its parent compound, tion, increased secretion of antidiuretic hor- phenacetin, chronic use can cause renal mone, and changes in the seizure thresh- damage—always a problem in adults with old. Synthetic narcotics such as penta- SS disease. zocine, butorphanol, and nalbuphine should be used with caution and should PAIN MANAGEMENT not be used in conjunction with other narcotics because they are agonist-antagonists Prevention and may induce withdrawal symptoms or Because all painful episodes cannot be pre- psychotomimetic effects. vented, patients should know how to man- Nonnarcotic analgesics are used to treat age mild pain and should be taught to rec- mild-to-moderate pain. In patients with ognize symptoms suggestive of serious severe pain, adding these analgesics to nar- problems. Optimal management of patients cotic therapy increases analgesia and has a with painful events requires adequate edu- significant narcotic-sparing effect. There- cation of the patient, family, and health fore, concurrent use of both is recommended. care providers. Conditions that expose the In particular, nonsteroidal anti-inflammatory patient to hypoxia, dehydration, and

extreme cold should be avoided. Mountain potent oral narcotics such as morphine, climbing, flying in unpressurized aircraft, hydromorphone, or oxycodone are rarely and swimming in frigid water are potential- indicated. Individual patients respond dif- ly hazardous. ArchiveIf air travel is necessary, ferently to specific analgesics, and open patients should be advised to travel in communication between physician and pressurized aircraft, refrain from alcohol patient is needed. Nausea does not repre- consumption,for historical maintain an increased Reference fluid sent allergy Only to oral narcotics. Patients truly intake, move about the plane periodically, allergic to codeine may be able to use oxy- and stay warm. Fluid intake (juices, soft codone. Whenever narcotic agents are drinks, and bouillon) should be increased given by repeated prescription, it must be during fevers, high ambient temperatures, established with the patient that such drugs and increased physical activity. will be obtained from one physician so that the use of the drug may be accurately Home-Based Management monitored. The majority of painful events can be man- A few patients request excessive amounts aged successfully at home, thus fostering of narcotics. Careful records of the number patient self-esteem and independence. The of tablets dispensed should be kept, and success of a home-based program depends records should be reviewed before pre- on patient education, including not only an scriptions are refilled. The number of explanation of the pathophysiology (“What tablets to be dispensed should be written happened?”) but also the expectations and in words (e.g., “ten,” not “10”), and it is limitations of such treatment (“When preferable to prescribe doses for a limited should I go to the hospital?”). In addition, period of time (i.e., a week, not a month). the patient should be taught to recognize the more serious complications of sickle Emergency Department cell disease to avoid delay in treatment. Management Complete home management programs The goals of emergency department man- include specific guidelines for oral fluid agement are to assess the clinical problem, intake and effective analgesics. Oral intake, treat the pain aggressively in a supportive often described in terms of ounces of fluid environment, and make an appropriate per day, should be at least 150 cc/kg/day diagnosis. High-risk patients should be for children and 3 to 4 L/day for adults. admitted directly to the hospital. The Soft drinks, juices, and bouillon are recom- guidelines for emergency department mended. Fluids devoid of electrolytes management are as follows: should not be the sole source of oral ■ Give appropriate analgesics in a titration hydration because they can produce an regimen to relieve pain and establish a electrolyte imbalance. useful regimen. Suggested doses and NSAIDs, acetaminophen, or aspirin are rec- intervals of administration are based on ommended for mild pain, with the precau- the severity of the pain (see Table 3). tions noted above. Codeine is the preferred ■ Administer IV fluids if necessary (see oral narcotic for more severe pain and “Hydration” above); closely monitor fluid should be given with nonnarcotics. More intake. The choice of fluids should be

Table 3 Recommended Dose and Interval of Analgesics Necessary To Obtain Adequate Pain Control in Sickle Cell Disease Archive DOSE/RATE COMMENTS Severe/Moderatefor Pain historical Reference Only 1. Morphine Parenteral: 0.1-0.15 mg/kg/dose every Drug of choice for pain, lower doses in 3-4 hours. Recommended maximum the elderly and infants and in patients single dose 10 mg. with liver failure or impaired ventilation. P.O.: 0.3-0.6 mg/kg/dose every 4 hours. 2. Meperidine (Demerol) Parenteral: 0.75-1.5 mg/kg/dose every Increased incidence of seizures. Avoid 2-4 hours. Recommended maximum in patients with renal or neurologic dis- dose 100 mg. ease or who receive monoamine oxi- dase inhibitors. P.O.: 1.5 mg/kg/dose every 4 hours. 3. Hydromorphone Parenteral: 0.01-0.02 mg/kg/dose every 3-4 hours. 4. Oxycodone P.O.: 0.04-0.06 mg/kg/dose every 4 hours. P.O.: 0.15 mg/kg/dose every 4 hours. 5. Ketorolac Intramuscular: Equal efficacy to 6 mg MS, helps nar- Adults: 30 or 60 mg initial dose, fol- cotic-sparing effect, not to exceed 5 lowed by 15 to 30 mg every 6-8 hours. days. Maximum 150 mg first day, 120 mg maximum subsequent days. May Children: 1 mg/kg load, followed by cause GI irritation. 0.5 mg/kg every 6 hours. 6. Butorphanal Parenteral: Agonist-antagonist. Can precipitate Adults: 2 mg every 3-4 hours. withdrawal if given to patients who are being treated with agonists. Mild Pain 1. Codeine P.O.: 0.5-1 mg/kg/dose every 4 hours. Mild-to-moderate pain not relieved by Maximum dose 60 mg. aspirin or acetaminophen; can cause nausea and vomiting. 2. Aspirin P.O.: Adults: 0.3-0.6 mg/dose every 4-6 Often given with a narcotic to enhance hours. Children: 10 mg/kg/dose every 4 analgesia. Can cause gastric irritation. hours. Avoid in febrile children. 3. Acetaminophen P.O.: Adults: 0.3-0.6 gm every 4 hours. Often given with a narcotic to enhance Children: 10 mg/kg/dose. analgesia. 4. Ibuprofen P.O.: Adults: 300-400 mg/dose every 4 Can cause gastric irritation. hours. Children: 5-10 mg/kg/dose every 6-8 hours. 5. Naproxen P.O.: Adults: 500 mg/dose initially, then Long duration of action. Can cause 250 every 8-12 hours. Children: 10 gastric irritation. mg/kg/day (5 mg/kg every 12 hours). 6. Indomethacin P.O.: Adults: 25 mg/dose every 8 hours. Contraindicated in psychiatric, neuro- Children: 1-3 mg/kg/day given 3-4 logic, renal diseases. High incidence of times. gastric irritation. Useful in gout.

designed to maintain adequate electrolyte anatomic distribution should be used along balance. with a sedation (level of consciousness) scale. ■ If the pain isArchive relieved for 3 to 4 hours, administer an oral narcotic and observe Fluid intake and urinary output should be for 1 hour. If moderate or severe pain monitored carefully, and patients should be returns,for repeathistorical the parenteral narcotic Referenceweighed Onlydaily. Due to the high risk of dose and observe. When pain is under acute chest syndrome, incentive spirometry control, give an adequate dose of an and pulse oximetry may be useful. The effective oral narcotic analgesic, if feasi- proper composition of the fluids should ble, using equi-analgesic dosing guide- maintain adequate electrolyte balance. lines. If relief is maintained, discharge Standard pain management with parenteral the patient with a small prescription and narcotics should be given by a patient-con- follow up within 1 week. If significant trolled technique. If a titration technique pain persists, admit the patient to the has not been instituted in the emergency hospital. A final dose of parenteral department, it should be initiated when the narcotics “for the road” is not patient is admitted to the floor and pain is recommended. not controlled. If PCAs are not used, nar- ■ Most hospitals have guidelines for the cotics should be given on a fixed schedule duration of a patient’s stay in the emer- (not as needed for pain), with rescue dos- gency department. These may be diffi- ing for breakthrough pain as needed. cult rules to follow in the case of Except when contraindications exist, con- patients with painful crises. Holding comitant use of NSAIDs should be standard areas for sickle cell disease are recom- treatment. Nurses should be instructed not mended to avoid unnecessary hospital- to give narcotics if the patient is heavily izations. Each patient’s management plan sedated or respirations are depressed. should be individually designed. When the patient shows signs of improve- Patients who require continuing treatment ment, narcotic drugs should be tapered with parenteral narcotics or who cannot gradually to prevent a withdrawal syn- take adequate amounts of fluid orally drome. It is usually advisable to observe require hospital admission. the patient on oral pain-relief medications for 12 to 24 hours before discharge from INPATIENT MANAGEMENT the hospital. A management plan should be developed There are several new methods for admin- by the responsible physician, written in the istering narcotics such as transdermal and hospital record, and discussed with the epidural administration of morphine. New patient and other personnel involved in the methods of narcotic administration may be patient’s management. It is important to attempted in institutions where there is record this information on a regular basis expertise in their use, where adequate in the hospital record and to help the monitoring is available, and appropriate patient develop coping skills. A pain mea- use of standard techniques has not resulted surement and description tool that evalu- in acceptable pain control. ates pain intensity, mood, distress, and

ALTERNATIVE PAIN MANAGEMENT painful episodes. It should not be used TECHNIQUES unless acidosis exists. Behavior modificationArchive programs, relaxation therapy, self-hypnosis, and transcutaneous Vasodilators electrical nerve stimulation may be helpful Vasodilators such as pentoxyphylline have adjuvant fortherapies historical for pain management. Referenceno proven efficacy Only in the management of Simple techniques such as relaxation and painful episodes. distraction are also helpful and can include music, audiotapes, and jaw relaxation exer- MANAGEMENT OF CHRONIC PAIN cises. Physical treatment such as massage A few patients almost always complain of and heat/cold therapy may be useful. pain. It is important to distinguish between These techniques may supplement but do acute and chronic pain. Treatment of not replace standard treatments. The suc- chronic pain as if it were acute is a danger- cess of these approaches may be deter- ous practice that can severely compromise mined by the patient’s commitment, com- the care of the patient in pain. These indi- pliance, and trust in the health care viduals may have an underlying medical provider. problem and should be extensively evaluated for a treatable condition such as occult ANXIETY AND SEDATIVE infection or collapsed vertebrae. Regardless MEDICATION of the etiology of pain, chronic depression Diazepam and chlorpromazine do not and anxiety are frequently present in these potentiate the analgesic effect of narcotics, patients and result in the loss of coping and their use should be avoided. skills. An adequate treatment plan should Hydroxyzine may potentiate the analgesic address these emotional factors and not or sedative effect of narcotics and may just the somatic pain. Psychiatric and social help selected patients. problems should be addressed by counseling. In addition, patients should be taught OTHER MEASURES alternative techniques of pain management and encouraged to participate in self-help Oxygen Therapy groups and vocational rehabilitation training programs. Continued transfusion thera- Oxygen (O2) therapy does not benefit py for chronic pain can result in serious vaso-occlusive episodes unless hypoxemia morbidity (e.g., iron overload) and should is present. In the absence of hypoxemia, be avoided. Tricyclic antidepressants may prolonged O2 therapy may induce be useful in chronic pain syndrome. These erythroid hypoplasia. drugs have a direct analgesic effect that occurs more quickly and at lower doses Sodium Bicarbonate than their antidepressant effect. They may also be useful in treating a neuropathic Sodium bicarbonate therapy has not been pain component that is refractory to other shown to improve the clinical course of treatment modalities.

PHYSICAL DEPENDENCE AND ITS addiction center, particularly one equipped CONFUSION WITH DRUG with comprehensive psychological and ADDICTION social support services. Methadone mainte- Archivenance without these support services is The fear of addiction is one of the greatest usually ineffective and should be avoided. obstacles to adequate pain control in sickle It should be remembered that drug-depen- cell disease, a fear that stems from inade- for historical Referencedent patients Only can have painful episodes; quate knowledge of the clinical pharmacol- management of such situations requires ogy of opioids. This lack of understanding compassion, firmness, and most important, promotes confusion between physical knowledge of opiate pharmacology. dependence and addiction. Addiction is a socio-psychological state that is character- BIBLIOGRAPHY ized by abnormal behavior pattern of drug abuse, by the craving of a drug for other Ballas SK. Treatment of pain in adults with than pain relief, by becoming overwhelm- sickle cell disease. Am J Hematol ingly involved in the procurement and use 1990;34:49-54. of the drug, and by the tendency to relapse Ballas SK, Delengowski A. Pain measure- after withdrawal. Drug tolerance is not ment in hospitalized adults with sickle cell addiction; it indicates that large doses of a painful episodes. Ann Clin Lab Sci narcotic are needed for an analgesic effect, 1993;23:358-61. often without expected adverse effects. Physical dependence is a physiologic Baum FK, Dunn DT, Maude GH, Serjeant response to the pharmacologic effects of GR. The painful crisis of homozygous sick- opioids characterized by the development le cell disease. A study of the risk factors. of withdrawal symptoms when an opioid is Arch Intern Med 1987;47:1231-4. abruptly discontinued or if an opioid antag- Benjamin LJ. Pain in sickle cell disease. In: onist is administered. Drug addiction there- Foley KM, Payne R (eds). Current therapy fore should not be the primary concern of of pain. Ontario, Canada: B C Decker, Inc., a physician treating patients with sickle cell 1989:90-104. disease for pain. The physician should focus on providing patients with adequate Benjamin LJ. Sickle cell disease. In: Max M, relief by understanding drug tolerance, Portenoy R, Laska E (eds). Advances in physical dependence, and the clinical phar- pain research and therapy. Vol 18. New macology of the drugs. This knowledge York: Raven Press, 1991. should translate into a practice that Cole TB, Sprinkle RH, Smith SJ, Buchanan includes tapering to prevent withdrawal, GR. Intravenous narcotic therapy for chil- thereby eliminating physical dependence dren with severe sickle cell pain crisis. Am after treatment for acute pain. Only occa- J Dis Child 1986;140:1255-9. sionally does true drug addiction develop Foley MK, Inturrisi EC. Analgesic drug ther- in patients with sickle cell disease. apy in cancer pain: principles and practice. Psychological, social, and economic factors Med Clin North Am 1987;71:207-32. are major forces in the patient’s addiction rather than the use of prescribed drugs. Gaukroger PB. Patient-controlled analgesia Addicted patients should be referred to an in children. In: Schechter NL, Berde CB,

Yaster M (eds). Pain in infants, children, Shapiro BS. The management of pain in and adolescents. Baltimore: Williams & sickle cell disease. Pediatr Clin North Am Wilkins, 1993:203-11.Archive1989;36:1029-45. Gil KM. Coping with sickle cell disease US Department of Health and Human pain. Ann Behav Med 1989;11:49-57. Services, Public Health Service, Acute Pain Management Guideline Panel. Acute pain Karko RF,for Foley historicalKM, Grabinsky PY, et al.Reference Only management: operative or medical proce- Central nervous system excitatory effects of dures and trauma. Rockville, Maryland: meperidine in cancer patients. Ann Neurol Agency for Health Care Policy and 1983;13:180-5. Research, 1992; AHCPR publication no. 92- Payne R. Pain management in sickle cell 0032. disease: rationale and techniques. Ann N Y White PF. Use of patient-controlled analge- Acad Sci 1989;565:189-206. sia for management of acute pain. JAMA Perlin E, Finke H, Castro O, et al. 1988;259:243-7. Infusional/patient-controlled analgesia in Yaster M, Tobin JR, Billett C, Casella JF, sickle-cell vaso-occlusive crises. Pain Clinic Dover G. Epidural analgesia in the man- 1993;6:113-9. agement of severe vaso-occlusive sickle Sandler DP, Smith JC, Weinberg CR, et al. cell crisis. Pediatrics 1994;93:310-5. Analgesic use and chronic renal disease. N Engl J Med 1989;320:1234-8.

CHAPTER 8 LUNG Archive for historical Reference Only

ACUTE CHEST SYNDROME CLINICAL DIAGNOSIS Acute chest syndrome is the second most Acute chest syndrome can develop as an common cause of hospital admission in isolated event or during the course of a patients with sickle cell disease and, in painful vaso-occlusive episode. Pleuritic some cases, represents a medical emer- chest pain is the dominant symptom in gency. It is an acute illness characterized adults. Fever, cough, and tachypnea are by new pulmonary infiltrates on the chest often the only findings in infants and x-ray and varying degrees of chest pain, young children. Involvement of the dyspnea, hypoxemia, fever, and prostra- diaphragmatic pleura can result in abdomi- tion. Because x-ray changes may take sev- nal pain. True lung pathology must be dif- eral days to appear, the diagnosis is com- ferentiated from sternal or rib infarction or monly recognized as it evolves and not cholecystitis. Although the pain of acute immediately on presentation. The term chest syndrome can mimic angina or “acute chest syndrome” is used because a myocardial infarction, coronary artery dis- more precise etiology is rarely document- ease is rare in children and young adult ed. In adults, acute chest syndrome usually patients. Depending on the extent of the results from pulmonary infarction etiologies pulmonary involvement, physical examina- such as bacterial or viral infection, fat/bone tion usually shows tachypnea, and there marrow embolism, intrapulmonary sickling, may be signs of pulmonary consolidation, and emboli of sickled red cells. In children, pleural effusion, or occasionally, a pleural it is better to assume an infectious etiology. friction rub. Alteration in mental status may Appropriate cultures and serological tests reflect hypoxemia and/or narcotic effect, should always be obtained. Recent bron- but it may also be seen in patients with choscopy-bronchial lavage data suggest systemic fat embolization. In severe cases that pulmonary fat embolism occurs in as in adults, the patient is often considered to many as 44 percent of patients with acute have adult respiratory distress syndrome. chest syndrome. Although the illness is frequently self-limited, particularly when it LABORATORY DIAGNOSIS involves a small area of pulmonary The chest radiograph of patients with acute parenchyma, it can rapidly progress and chest syndrome shows infiltrates in one or may be fatal. Frequent chest syndrome more lobes (66 percent have single lobe episodes indicate severe sickle cell disease involvement). Pleural effusion occurs in 15 and predict early mortality in adults. percent of the cases. Radiographic studies

may be normal or nondiagnostic during the in antibody titers may help suggest the eti- first 2 to 3 days, especially if the patient is ology. A viral etiology is more likely in dehydrated. Cultures of blood, sputum, or winter, but mycoplasma are more common pleural fluid occasionallyArchive reveal a bacterial in the fall. If sputum or bronchial lavage pathogen. Measurement of arterial blood specimens are obtained, they should be gases rather than ear or pulse oximetry stained for fat. A positive result suggests fat may be necessaryfor historical for initial assessment Reference of embolism. Lung Only scans generally are not the severity of the illness and for subse- useful in diagnosing the etiology of acute quent clinical management. Initial samples chest syndrome or in making a therapeutic should be taken while the patient is breath- decision. Due to the hypertonicity of most ing room air. Because patients with sickle contrast dyes, pulmonary angiography car- cell disease may have a low arterial oxygen ries the theoretical risk of increased sickling; therefore, the procedure is rarely pressure (pAO2) during the steady state, the interpretation of low oxygen tension can indicated. be difficult unless arterial gas measurements have been previously obtained. CAUSES OF “CHEST SYNDROME” However, severe hypoxemia (pAO2 below 1. Hemoglobin S related 60 mmHg in an adult or below 70 mmHg in a child) indicates potentially life-threat- a. Direct consequence ening disease, particularly if it does not i. Pulmonary infarction - in situ improve with oxygen administration. In sickling patients receiving oxygen by face mask, aa. etiology unknown the severity of the pulmonary process can bb. hypoventilation 2o to be assessed by calculating the A-a O2 gra- dient. If noninvasive oximetry is used to (i) rib/sternal infarction monitor trends, it is most helpful in conjunction with periodic arterial blood gas (ii) narcotic administration measurements. (iii) postoperative Complete blood counts, including reticulo- atelectasis. cyte counts and leukocyte differential ii. Embolism infarction counts, should be obtained serially. An aa. necrotic bone marrow/fat increased neutrophil count above baseline level and a shift to the left suggests a bac- bb. sickled cells from distal site terial infection. A falling hematocrit, with or (i.e., liver sinuoids). without reticulocytosis, is commonly seen iii. Pulmonary edema 2o to fluid as the syndrome evolves and may con- overload. tribute to tissue hypoxia. b. Indirect consequence-infection In children, S. pneumoniae is less common as a cause of this syndrome than it was i. Bacterial before prophylactic penicillin and the ii. Viral pneumococcal vaccine were used. In most adult cases, no pathogen is isolated. iii. Fungal Isolation of mycoplasma or viruses or a rise iv. Protozoan

2. Unrelated to Hb S pneumoniae and H. influenzae. Depending on the local susceptibility pattern of these a. Thromboembolism (from throm- organisms, and whether the patient was on bosed vein) Archiveprophylactic penicillin, an appropriate b. Opportunistic infection related to combination of penicillin, cephalosporin, or forHIV historical infection Referencevancomycin Only should be used. Oral eryth- c. Bronchial obstruction 2o to foreign romycin should be added if Mycoplasma body or neoplasm pneumonia is suspected. Adjustment of the antibiotic regimen will depend on the d. Acute sarcoidosis results of the bacterial cultures. e. Other: aspiration, trauma, etc. Exchange transfusions should be performed if the patient develops multiple Treatment lobe involvement, rapidly progressing dis- All patients with acute chest syndrome ease, or signs of respiratory insufficiency must be admitted to the hospital. (pAO2 below 60 mmHg in an adult or Depending on the extent of lung involve- below 70 mmHg in a child while breathing ment and respiratory distress, the intensive oxygen) (see Chapter 10, Transfusion). care unit may be required for appropriate Patients with chronic hypoxemia, as deter- monitoring of a rapidly changing clinical mined by baseline studies, should be con- state. Analgesics should be administered; sidered for exchange transfusions when however, narcotic-induced hypoventilation there is a drop greater than 25 percent must be avoided. A delicate balance must from the steady-state pAO2. If progressive be found to provide pain relief and elimi- severe anemia develops in a patient with nate splinting without causing hypoventila- borderline abnormal pulmonary function, a tion. Overhydration may be as dangerous simple transfusion of packed red blood as dehydration, and intravenous fluids must cells may be required. Unless thromboem- be cautiously administered. Oxygen thera- bolism is proved, anticoagulant therapy is py is indicated for hypoxemia, tachycardia, not recommended. and tachypnea, and it should be monitored by frequent measurement of arterial blood SYSTEMIC FAT EMBOLIZATION gases. Patients may become profoundly SYNDROME hypoxic if they remove their oxygen masks Systemic fat embolization syndrome is a for eating or bathing. Nasal prongs may be rare, but often fatal, complication that is used in these instances, but the amount of due to widespread embolization of liquified oxygen actually inspired will be lower than necrotic bone marrow fat into the pul- with a face mask. monary vessels and then to the systemic It is often impossible to make a reliable a circulation (see Stroke, Chapter 9). Patients priori differentiation between pulmonary with sickle cell disease can develop the infarction and bacterial pneumonia. In 2 to syndrome during a severe vaso-occlusive 5 percent of the cases, acute chest syn- episode. Symptoms include bone pain, drome is associated with a positive blood fever, chest pain, dyspnea, confusion, agita- culture; the most common isolates are S. tion, and coma, with or without acute renal

failure. In some cases, disseminated radiograph demonstrating increased intravascular coagulation with severe parenchymal markings or fibrosis, and microangiopathic hemolytic anemia and chronic hypoxia. Repeated episodes of multiorgan failure canArchive occur. midline, severe, crushing chest pain signal myocardial ischemia (without coronary A high index of suspicion is essential for artery disease). With recurrent episodes of early diagnosis. Pulmonary fat embolization for historical Referenceacute chest syndrome, Only the patient develops can be detected by the finding of intracel- pulmonary hypertension and heart failure. lular lipid in secretions obtained by A chronic transfusion program may reduce bronchial lavage. Demonstration of necro- the frequency of recurrent attacks of chest sis on marrow aspirates, presence of refrac- syndrome, and nocturnal oxygen therapy tile bodies on fundoscopic examination, may be helpful in selected patients. head and neck petechiae, and fat globules in the urine can be helpful in establishing BIBLIOGRAPHY the diagnosis. If the diagnosis is suspected, early institution of exchange transfusions Bellet P, Kalinyak K, Shakla S, et al. accompanied by supportive treatment may Incentive spirometry to prevent acute pul- be lifesaving. monary complication in sickle cell disease. N Engl J Med 1995;333:699-703. ASTHMA Bhalla M, Abboud MR, McLoud TC, et al. Asthma and chronic asthmatic bronchitis Acute chest syndrome in sickle cell disease: pose a potential therapeutic problem in CT evidence of microvascular occlusion. sickle cell disease patients. Epinephrine use Radiology 1993;187:45-9. is associated with increasing heart rate and Castro O, Brambilla DJ, Thorington B, et al. can compromise cardiac stroke output. The The acute chest syndrome in sickle cell dis- diuretic action of some bronchodilators ease: incidence and risk factors. The may dehydrate the patient, but these agents Cooperative Study of Sickle Cell Disease. are usually required. Hydration is essential, Blood 1994;84:643-9. and intravenous fluids should be administered early during an asthma attack that Gelfand MJ, Daya SA, Rucknagel DL, et al. does not quickly resolve. Long-term man- Simultaneous occurrence of rib infarction agement is not different from that for indi- and pulmonary infiltrates in sickle cell dis- viduals without sickle cell disease. ease patients with acute chest syndrome. J Nuclear Med 1993;34:614-8. CHRONIC RESTRICTIVE LUNG Johnson CS, Verdegem TD. Pulmonary DISEASE complications of sickle cell disease. Semin Chronic restrictive lung disease, with pul- Resp Med 1988;9:287-96. monary hypertension and cor pulmonale in Powars D, Weidman JA, Odom-Maryon T, late stages, is a consequence of previous Niland JC, Johnson C. Sickle cell chronic vaso-occlusive episodes and has a poor lung disease: prior morbidity and the risk prognosis. Diagnosis before the clinical of pulmonary failure. Medicine 1988;67:66- onset of cor pulmonale is based on 76. abnormal pulmonary function tests, chest

Sprinkle RH, Cole T, Smith S, Buchanan Vichinsky E, Williams R, Das M, et al. GR. Acute chest syndrome in children with Pulmonary fat embolism: a distinct cause of sickle cell disease. A retrospective analysis severe acute chest syndrome in sickle cell of 100 hospitalizedArchive cases. Am J Pediatr anemia. Blood 1994;83:3107-12. Hematol Oncol 1986;8:105-10. for historical Reference Only

Archive for historical Reference Only

CHAPTER 9 STROKE Archive for historical Reference Only

Clinically evident stroke is a devastating a vascular distribution. Typically, there is complication of SS disease that affects from no clinically apparent residual deficit from 6 to 12 percent of patients. Strokes are very a TIA, though newer imaging modalities rare in persons with Hb SC disease. In chil- such as MRI and positron emission tomog- dren under age 10 years, the most common raphy (PET) have identified ischemic brain cause of stroke is cerebral infarction. lesions in both the gray and white matter Ischemic stroke typically presents with in some patients. TIA often is a harbinger signs and symptoms of hemiparesis or of subsequent stroke. monoparesis, hemianesthesia, visual field deficits, aphasia, cranial nerve palsies, or PATHOPHYSIOLOGY acute change in behavior. Although recov- Infarction usually occurs in a segmental ery occasionally is complete, intellectual, pattern that suggests damage to the large motor, and sensory impairments are typical cerebral arteries. The most common abnor- sequelae. Intracranial hemorrhage becomes malities found on arteriography or magnet- increasingly more common with advancing ic resonance angiography (MRA) are age. In hemorrhagic stroke, more general- marked narrowing or complete occlusion ized phenomena such as coma, headache, of the anterior cerebral arteries (ACA) and seizures occur. Recurrent stroke causes and/or middle cerebral arteries (MCA). progressively greater impairment and Multiple, bilateral vessel involvement is increased likelihood of mortality. A “completed stroke” signifies a fixed neurologic usual, even in patients who have unilateral deficit, whereas “stroke in progression” neurologic signs. Vessel narrowing is the implies worsening of the neurologic deficit consequence of intimal and medial prolifer- or appearance of new focal abnormalities ation that is thought to be caused by while the patient is under observation. endothelial damage from sickled red blood Nonfocal complaints such as dizziness, cells. The damaged, irregular endothelium headache, or fainting are not in themselves can serve as a nidus for the adhesion of representative of cerebral vascular disease platelets and sickle cells, thereby resulting but should be investigated carefully. in thrombus formation. The stroke event occurs when narrowing is severe enough A transient ischemic attack (TIA) is a focal to compromise distal flow or the thrombus neurologic deficit persisting for less than 48 dislodges and causes distal embolization. hours (24 hours for internal carotid, anteri- Transient neurologic symptoms can result or, or middle cerebral arteries and 48 hours from vessel spasm. for vertebral or basilar arteries) that follows

Intracranial hemorrhage can be intracere- risk. In emergency situations, partial or bral or subarachnoid and can result from total exchange transfusion can be used to rupture of an aneurysm of the circle of lower the level of Hb S rapidly (see Willis. Intracerebral Archivehemorrhage may also Chapter 10, Transfusion). It is uncertain occur years later in patients who had prior whether CT scanning with intravenous cerebral infarction as a result of a rupture infusion of the new contrast agents with of fragilefor collateral historical vessels (moyamoya). Referencereduced osmolarity Only is less hazardous in untransfused patients. DIAGNOSIS CT scan or MRI/MRA should be performed A high-resolution, computerized tomo- on patients who experience a TIA. Patients graphic (CT) scan performed as an emer- with persistent or severe headaches, synco- gency diagnostic procedure without con- pal episodes, or seizures deserve thorough trast may be normal at the onset in cere- evaluations, often by a neurologist, and bral infarction but is helpful in ruling out may need neurologic imaging. Transcranial bleeding, abscess, tumor, or other abnor- Doppler studies or ultrasonography of the malities. The CT scan 2 to 7 days later typi- large cerebral vessels may reliably predict cally is able to demonstrate the area of the patient who is at risk for stroke when infarction. MRI is a sensitive technique for narrowing of the MCA or ACA is identified. detecting intracranial hemorrhage or infarc- The prognostic value of newer techniques tion. MRA permits visualization of major such as PET or metabolic MRI are under intracerebral vessels without the potential intensive investigation. Data suggest that hazards of hypertonic contrast materials. abnormalities on metabolic MRI scans or However, MRI/MRA scanning requires PET scans in SS patients, who do not have more time at the imaging center than CT overt neurologic deficits, may be useful in scanning, and high-resolution equipment identifying patients at risk for progression (1.5 tesla or more) is required. Lumbar of the cerebral vasculopathy and future puncture, which should be done only if a strokes. A schema for evaluating neurologi- CT scan or MRI reveals no evidence of cal events is displayed in figures 1 and 2. increased intracranial pressure, is occasionally necessary to eliminate infection or sub- TREATMENT OF ACUTE VASO- arachnoid hemorrhage as the cause of the OCCLUSIVE STROKE stroke. For the patient with acute occlusive stroke, Arteriography is not necessary to confirm rapid evaluation and careful monitoring are cerebral infarction demonstrated by CT essential. Patients should be admitted to an scan, MRI, or MRA, but it can be helpful in intensive care unit. Raised intracranial pres- clarifying the diagnosis in the rare sympto- sure should be treated promptly with phar- matic (hemiparesis) patient with normal CT macological agents. Assisted ventilation or MRI scans. Use of hyperosmolar contrast may be necessary. Hyperventilation thera- material makes arteriography potentially py, however, should be avoided. The hazardous in patients with sickle cell dis- involvement of a neurologist and/or neuro- ease. Adequate hydration, reduction of the surgeon is essential. Seizures are common Hb S level to less than 30 percent by trans- during acute infarction and hemorrhage fusion, and close supervision decrease the and require anticonvulsant therapy.

ArchiveStroke With Neurologic Deficit for historicalImmediate Without Reference Contrast CT, or MRI/MRA Only

Hemorrhage Infarction Negative

MRA or Transcranial Angiography Doppler (TCD)

Repeat MRI/MRA in 7 Days, or PET

Positive Negative

Angiography

Figure 1 Algorithm for evaluating clinical stroke.

Transcient Ischemic Other Neurologic Events Attack in Afebrile Patients

Thorough Serial MRA/MRI Evaluations

Positive Negative Transcranial Doppler

Consider TCD, PET, Imaging as indicated and/or Arteriography MRI, MRA, or PET

Figure 2 Algorithm for evaluating transcient ischemic attacks and repeat afebrile seizures.

Exchange transfusion to decrease the level therapy for these patients is unclear at of Hb S to less than 30 percent may help present. to prevent progression of the acute stroke. ArchiveInadequate transfusion therapy, as defined In addition to transfusions, it is important by a failure to suppress Hb S below 30 to provide rehabilitation services to the percent, may be due to inadequate fre- patient. Althoughfor historical many children may Referencequency of transfusions, Only poor compliance, exhibit remarkable recovery from a stroke, development of alloimmune or autoimmune a detailed assessment of intellectual func- antibodies, or blood loss. tion should be done to determine if the Although aspirin or coumadin therapy has child would benefit from special assistance been effective in decreasing the risk of with academic work because acquired learn- recurrent stroke in adult patients with nor- ing difficulties may be the consequence of mal hemoglobin (AA), or in those who the stroke. have had prior TIA, the efficacy of such therapy in central nervous system disease PREVENTION OF RECURRENT in patients with sickle cell disease has not OCCLUSIVE STROKE been established. Vaso-occlusive strokes will recur in at least two-thirds of patients, unless they are HEMORRHAGIC STROKE placed on a chronic program. Transfusions Patients with intracranial hemorrhage (IH) of packed red blood cells given at regular may present with focal neurological intervals to keep the level of Hb S below deficits, severe headache, increased 30 percent are effective in minimizing a intracranial pressure, or coma. Immediate recurrence of cerebral infarction in chil- mortality is as high as 50 percent. This is a dren. A transfusion program should be frequent cause of sudden unexpected maintained for a minimum of 5 years. death at home. In patients with end-stage Should neurologic symptoms develop in renal failure from sickle cell disease, IH is adequately transfused patients, repeat a common cause of death. Immediate CT imaging studies are warranted. The optimal or MRI scanning should demonstrate the duration of transfusion therapy is not hemorrhage. Lumbar puncture may be nec- known. The risk of recurrence in untrans- essary to demonstrate the subarachnoid fused children is greatest in the first 3 years hemorrhage (blood in cerebrospinal fluid) after the initial event. Many centers trans- in some patients. Because vasospasm in fuse patients for years but modify the the area of hemorrhage can produce sec- intensity of transfusions to reduce the rate ondary cerebral infarction, immediate of iron accumulation. Centers that transfuse exchange transfusion is recommended. patients for long periods use iron-chelating There are no data regarding the efficacy of agents (deferoxamine mesylate) to decrease long-term transfusion therapy for patients iron overload. Prognosis for long-term neu- with IH. In those patients who are not ure- rologic function and independent self-suffi- mic, arteriography is necessary to deter- cient adult life is guarded. The role of bone mine if a surgically correctable lesion marrow transplantation as an alternative (aneurysm) is present.

IDENTIFICATION OF PATIENTS AT exhibit decorticate, or even decerebrate, RISK FOR STROKE posturing. Abnormal cerebralArchive blood flow assessed by ■ Signs of acute tissue injury such as transcranial Doppler ultrasonography has necrosis of the bone marrow, acute cen- been shown to be predictive of stroke in trilobular necrosis of the liver, renal dys- patientsfor with historical sickle cell disease. IncreasedReferencefunction, Only and severe acute chest syn- flow rates in the intracerebral arteries is drome (see Chapter 8). secondary to stenosis and is associated ■ Elevated serum lipase and fat globules in with an increased risk for infarctive stroke. urine during early stages. Current studies are evaluating the role of routine MRIs in asymptomatic children to ■ Normalization of the signs of acute tissue identify those with cerebrovascular changes injury and the neurological examination (see Chapter 23). over a period of 1 to 3 weeks. This syndrome must be treated rapidly and ACUTE COMA DUE TO aggressively. Complete exchange transfu- GENERALIZED ARTERIAL sion is thought to be useful. Aggressive HYPOXEMIA treatment of hypoxia, including the use of Uncommonly, patients with Hb SS and its positive end-expiratory pressure (PEEP) or variants may exhibit a multiorgan dysfunc- oscillating ventilatory devices if necessary, tion syndrome following arterial hypoxia is essential as well as management in an that is usually induced by acute and pro- intensive care unit. gressive pulmonary disease. The syndrome (often caused by “fat embolism” or bone BIBLIOGRAPHY marrow necrosis) apparently arises from Adams R, McKie V, Nichols FT, et al. The the sickling of erythrocytes in the arterioles use of transcranial ultrasonography to pre- of the bone marrow, causing fat and bone dict stroke in sickle cell disease. N Engl J marrow embolism. In the brain, there is Med 1992;326:605-10. sufficient resultant hypoxia to cause neu- ronal dysfunction but not necrosis; hence, Anson JA, Koshy M, Ferguson L, Crowell the process can be reversible. Multiorgan RM. Subarachnoid hemorrhage in sickle failure is characterized by the following: cell disease. J Neurosurg 1991;75:522-88.

■ Often preceded by the most excruciating Craft S, Schatz J, Glauser TA, Lee B, pain that the patient has ever experi- DeBaun MR. Neuropsychological effects of enced. stroke in children with sickle cell anemia. Pediatrics 1993;123:712-7. ■ High mortality rate within the first week. Koshy M, Thomas C, Goodwin J. Vascular ■ Upper extremity and facial petechia lesions in the central nervous system in (often missed). sickle cell disease (neuropathology). J Assoc ■ A rapid progressive, generalized neuro- Acad Minor Phys 1990;1:71-8. logical deterioration, generally without Pavlakis SG, Prohovnik I, Piomelli S, focal neurological signs, that can DeVivo DC. Neurologic complications in progress to coma. The patients may

sickle cell disease. Adv Pediatr 1989;36:247- Wang WC, Kavnar EH, Tonkin IL, et al. 76. High risk of recurrent stroke after discon- tinuance of five to twelve years of transfu- Powars D, Wilson B, Imbus C, Pegelow C, Archivesion in patients with sickle cell disease. J Allen J. The natural history of stroke in Pediatr 1991;118:377. sickle cell disease. Am J Med 1978;65:461. Wiznitzer M, Ruggieri PM, Masaryk TJ, Ross Russel MO,for Goldberg historical HI, Hodson A, et Reference al. Only JS, Modic MT, Berman B. Diagnosis of Effect of transfusion therapy on arterio- cerebrovascular disease in sickle cell ane- graphic abnormalities on the recurrence of mia by magnetic resonance angiography. J stroke in sickle cell disease. Blood Pediatr 1990;117:551-5. 1984;63:162.

CHAPTER 10 TRANSFUSIONArchive for historical Reference Only

Transfusion should be used for specific INDICATIONS FOR TRANSFUSIONS indications in the treatment of patients with The following are generally considered to sickle cell disease and should be used as be indications for red blood cell transfu- sparingly as possible. Transfusion is sions in sickle cell disease: indicated for certain acute problems (not including acute painful episodes) or for the ■ In severely anemic patients, transfusions treatment or prevention of chronic compli- should be simple transfusions without cations and other health-related events. exchange, hence, without removal of Several methods of transfusion are avail- any blood from the patient. Simple trans- able (simple transfusion, partial exchange, fusions of this sort should be considered and chronic exchange); the method used in the following situations: depends on the indication for the transfu- — In patients who are so anemic that sion. The recommendations in this discus- they have physiological derangement sion are for patients with homozygous SS that is manifest by impending or βo disease and S thal. The role of transfu- overt high output cardiac failure, dys- sion in the care of patients with Hb SC dis- pnea, postural hypotension, angina, β+ ease and Hb S thalassemia is controversial. or cerebral dysfunction. An important principle in the transfusion of — In patients who have had a sudden sickle cell patients is the avoidance of diminution in hemoglobin concentra- excessive blood viscosity. Blood viscosity is tion, particularly patients having an a function of the intrinsic viscosity of the acute splenic or hepatic sequestration red blood cells and of the hematocrit. crisis, manifest by rapid splenic or Because sickle cells are intrinsically less liver enlargement and rapidly falling deformable than normal cells, raising the hematocrit. hematocrit without substantially reducing — In patients who exhibit fatigue and the proportion of sickle cells may raise the dyspnea, usually at hemoglobin con- blood viscosity to dangerous levels. centrations less than 5.0 g/dL and a Therefore, simple transfusions should be hematocrit less than 15 percent, par- used with caution in patients with high ticularly in association with erythroid hematocrits, and the final posttransfusion hypoplasia or aplasia. hematocrit should be 36 percent or less. Patients with high baseline hemoglobin ■ When there is a need to improve may be more safely transfused using an microvascular perfusion by decreasing exchange technique. the proportion of erythrocytes containing

Hb S, an exchange transfusion is indicat- EQUIVOCAL INDICATIONS ed unless the patient is severely anemic Transfusion is sometimes suggested for a and has good cardiac function. Such number of conditions in which its efficacy conditions includeArchive both acute and is unproved. If transfusion is done in these chronic conditions: conditions, it should be an exchange — Acutefor or suspectedhistorical cerebrovascular Referencetransfusion. These Only conditions include the accidents and TIA (see Chapter 9, following: Stroke). ■ Intractable or frequent painful events. — Multiorgan failure syndrome, including ■ “fat embolization.” Situations in which the patient’s condition is deteriorating rapidly, and all other — Acute chest syndrome or other acute treatments have been unsuccessful. lung disease when arterial oxygen ■ cannot be maintained at near-normal Before injection of hypertonic contrast levels with oxygen therapy or when material. the process progresses, despite ■ Adults who have had a cerebrovascular antibiotic and other indicated accident. therapy. ■ Leg ulcers (see Chapter 16, Leg Ulcers). — Acute priapism unresponsive to ■ Complicated pregnancy. therapy. ■ Chronic organ failure. — Surgery on the posterior segment of the eye, even when done under local ■ Extreme diminution in performance sta- anesthesia in a nonanemic patient tus due to recurrent complications of (see Chapter 12, Eye). Transfusion is sickle cell disease. not needed for laser surgery. When chronic transfusion programs are — Preparation for general anesthesia stopped, many patients have an exacerba- (see Chapter 21). tion of symptoms that may last for several weeks to months. If these symptoms ■ Chronic transfusion programs, usually become excessive or threatening to a initiated by exchange transfusion, are patient’s health, the transfusion program indicated for several conditions. In these may need to be reinstituted and then programs, an effort is made to maintain stopped more gradually, although the the percentage of Hb A above 50 to 70 physiologic justification may be unclear. percent, which usually requires repeated transfusions every 3 to 4 weeks. NONINDICATIONS AND Indications for a chronic transfusion pro- CONTRAINDICATIONS gram include: The following are not considered appropri- — Children who have had a cerebral ate indications for transfusion, and transfu- vascular accident for the prevention of further complications. sion is not recommended in these clinical settings: — Chronic congestive heart failure in conjunction with other treatment.

■ Chronic steady-state anemia. Most All patients with a history of prior transfu- patients with sickle cell disease are rela- sion should be screened for the presence tively asymptomatic from their anemia of alloantibodies. The efficacy of a chronic and do not Archiverequire transfusions to transfusion program should be assessed improve oxygen-carrying capacity. periodically by determining the proportion of Hb S by quantitative hemoglobin elec- ■ Uncomplicated acute painful crises. for historical Referencetrophoresis Only as well as the hemoglobin ■ Infections. concentration or hematocrit. ■ Minor surgery not requiring prolonged Red blood cell preparations depleted of general anesthesia (e.g., myringotomy, leukocytes by filtration are recommended simple biopsy). because of the reduction in febrile reac- ■ Aseptic necrosis of the hip or shoulder tions and decreased alloimmunization to (except when surgery is required). leukocyte antigens. Washed red blood cells should be used in patients who have a his- ■ Uncomplicated pregnancy. tory of severe allergic reactions (bron- chospasm) following prior transfusions. TYPES OF BLOOD PRODUCTS TO BE USED The use of autologous blood transfusions in sickle cell disease should be avoided. Standard bank blood is appropriate for the Blood relatives should not be used as patient with sickle cell disease. The “age” blood donors for children who may be of the blood (time since collection) is usually not important as long as it is within candidates for bone marrow transplantation. limits set by the transfusion service. Exchange transfusion with blood less than TRANSFUSION METHODS 5 days old (less than 3 days old in the small infant) helps in acute situations Simple Transfusion requiring immediate correction of the oxy- Simple transfusions can be used for acute gen-carrying capacity. All blood should be anemia or hypovolemia or in a chronic screened for the presence of sickle hemo- transfusion program. Packed red blood globin and confirmed to be negative. A sol- cells should not be used when only vol- ubility test is adequate for screening in this ume expansion is needed. situation. This procedure eliminates blood with sickle cell trait, which will confuse Exchange Transfusion later measurements of the proportion of sickle cells or Hb S. The antigenic pheno- Exchange transfusion is used to alter the type of the red cells (at least ABO, Rh, hemoglobin level rapidly and to replace Kell, Duffy, Kidd, Lewis, Lutheran, P, and sickle cells with normal erythrocytes. This MNS groups) should be determined in all type of transfusion reduces the concentra- patients older than 6 months of age. A per- tion of sickle cells without substantially manent record of this should be main- increasing the hematocrit or whole blood tained in the Blood Bank, and a copy of viscosity. Several methods are available that the record should be given to the patient achieve this purpose. or family.

Rapid Partial Exchange The devices used in plasmapheresis can be used to exchange transfuse patients effi- In some patients, whole blood can be ciently; red blood cells are removed at the removed from one arm at the same time Archiveegress and normal blood is infused at the that donor cells are transfused into the other arm. In adults, this procedure can be ingress. Usually six to eight units of blood performedfor in 500 historical mL units. In children, Reference the are needed to Onlyexchange an adult; formulae individual exchange aliquots are adjusted are available to calculate the exact amount to a safe and practical level. needed depending on body size, hematocrit, desired hematocrit, and desired per- The total volume of blood to be used is centage of Hb A. Such devices can be used proportional to the patient’s body weight for pediatric patients if the size of the and hematocrit; thus, different formulas are receptacle is sufficiently small so as not to needed for different initial hematocrit remove too much blood at one time. ranges. Exchange transfusions performed with whole blood (or, more commonly, Care must be taken in all cases where packed cells reconstituted to the volume exchange transfusion is used to be certain and hematocrit of whole blood using saline that the final hemoglobin level does not or other diluents) are more efficient than exceed 10-12 g/dL to avoid the problems those using packed cells. They may reduce of hyperviscosity. Careful monitoring of the the number of units needed but take slight- level of hemoglobin and of the percentage ly more time. In children, a practical esti- of Hb A is necessary to be certain that the mate of the volume required for exchange goals of the transfusion have been met. (whole blood or packed cells reconstituted to a hematocrit of 30 to 40 percent) is 50- Chronic Transfusion Programs 60 mL/kg. In adults, blood can be removed Once a sufficient level of transfused normal from the patient in 500 mL aliquots, fol- cells (greater than 50 to 70 percent Hb A) lowed by infusion of 500 mL of reconstitut- is achieved, it is often useful to maintain ed blood; this may be repeated for six to this for a period of weeks to years. This eight units of transfusion. Alternatively, the following technique can be used: proportion of normal cells can be maintained by simple transfusions at intervals of Step 1. 2 to 4 weeks. The level of Hb A must be Bleed one unit (500 mL) of blood from the monitored by quantitative hemoglobin patient, infuse 500 mL of saline. electrophoresis.

Step 2. TRANSFUSION COMPLICATIONS Bleed a second unit from the patient, infuse two units of blood. Transfusion complications for sickle cell patients are the same as those for any Step 3. patient receiving acute or chronic Repeat steps 1 and 2; if the patient has a transfusion. large red blood cell mass, repeat once more.

Volume Overload with sickle cell anemia is approximately 20 to 25 percent, which is greater than in the This occurs when too much volume is general population. This condition causes transfused too quickly. Congestive heart Archivedifficulty in obtaining compatible blood failure and pulmonary edema are most likely to occur in patients who have cardiac and results in a high incidence of delayed dysfunctionfor historical or minimal cardiac reserve. Referencehemolytic Only transfusion reactions. The Administration of intravenous furosemide delayed transfusion reaction occurs 5 to 20 and partial removal of red cell preserving- days after transfusion and is due to anti- fluid before transfusion and a slow transfu- bodies not detectable at the time of com- sion rate can help in preventing this serious patibility testing. It has been found that 30 problem. percent or more of the antibodies to red blood cell antigens may disappear with time, although the recipient remains capa- Iron Overload ble of mounting an anamnestic response to The serum ferritin levels should be mea- further stimulation by transfusion. The sured periodically. If the level exceeds delayed hemolytic transfusion reaction that 2,000 ng/mL (usually after 1 to 3 years of can result may cause severe anemia, onset chronic transfusion) and transfusions are of painful crisis, or even death. still required, patients should be considered for chronic chelation therapy using ACUTE HEMOLYTIC TRANSFUSION Desferal. Complications of deferoxamine REACTIONS therapy may include ototoxicity, ophthalmic toxicity, allergic reactions, growth Acute hemolytic transfusion reactions in failure, unusual infections (Yersinia, fungi), sickle cell patients are not different in and pulmonary hypersensitivity. Poor cause from those in other patients. Major patient compliance, because of repeated hemolytic reactions occur primarily with subcutaneous infusions of medications, is a major blood group (ABO) mismatches and significant problem with chronic chelation must be treated aggressively to maintain therapy. Ongoing education and support, blood pressure and glomerular filtration; often provided by a specially trained nurse, most can be prevented by avoiding clerical is usually necessary to maintain the and patient or sample identification errors patients’ cooperation. A subcutaneous infu- in the cross-matching and transplantation sion port or a Hickman catheter may be of units from donor site to the patient. used for parenteral access. Desferal therapy Minor hemolytic reactions occur when the should be discontinued during acute bacte- amount of antibody in the serum is limit- rial infections. A new oral iron chelator (L- ing, and they are characterized by the dis- 1) is currently being evaluated for safety appearance of the transfused blood during and efficacy. a period of several days (with a consequent decrease in the hematocrit) and the Alloimmunization and Delayed appearance of hyperbilirubinemia; no fur- Hemolytic Transfusion Reactions ther treatment is necessary except monitoring the hematocrit level to ensure that it The incidence of alloimmunization to red does not greatly decrease. blood cell antigens in transfused patients

Any of these reactions, particularly the and community groups can assist in delayed variety, are able to initiate a accomplishing this objective. painful episode in the patient with sickle The patient alloimmunized to one red cell disease. In all cases,Archive the patient’s blood blood cell antigen is more likely to become should be examined very carefully by alloimmunized to others, and care should immunohematologistsfor historical in the transfusion Referencebe taken in selecting Only transfusion units. service to document the antibody or anti- Transfusions should be given only for bodies responsible for the reaction; the clearcut indications. These patients should patient must be made aware of the compli- be counseled to advise any new physician cation and be given a card describing the of their history of alloimmunization. antibodies found. Carrying a card or an identification bracelet Alloimmunization and hemolytic transfu- listing the red blood cell phenotype and sion reactions resulting from it can be any identified antibodies is strongly reduced by the following: recommended.

■ Acquiring and maintaining adequate records of previous transfusions and Autoimmune Anemia Following complications arising from them. Allosensitization

■ Limiting the number of transfusions In some highly alloimmunized patients, a administered. syndrome of autoimmune hemolytic anemia may follow allosensitization or a ■ Screening for newly acquired antibodies hemolytic transfusion reaction. In this case, 1 to 2 months after each transfusion to the patient may become more anemic than detect transient antibodies capable of before transfusion, and the direct antiglob- causing a subsequent delayed reaction. ulin (Coombs’) test remains positive even ■ Diminishing the opportunities for alloim- after the incompatible transfused cells have munization because of a mismatch in the been destroyed. This syndrome occurs antigens of donors and patients: because the body produces antibodies against self-antigens, and it may persist — Typing the patient before the transfu- from several weeks to 2 to 3 months sion (if this has not already been before disappearing. Further transfusion is done) for antigens of the Rh and Kell complicated by the autoimmune antibody blood groups and avoiding the trans- and requires sophisticated blood-banking fusion of cells bearing these antigens techniques to find the “least incompatible” (particularly E, C, and Kell) if the blood for transfusion. patient lacks the antigen. More complete antigen matching has been suggested, but it is expensive and the Alloantibodies to White Cells, utility of such matching is not clear. Platelets, and Serum Proteins — Increasing the use of African- Patients who are transfused may become American donors of blood because of alloimmunized to antigens present on the similarity of red blood cell anti- leukocytes and/or platelets but lacking on genic phenotypes. Family members red blood cells. Such antibodies may cause

a febrile reaction that can be prevented occurred in approximately one-third of through the removal of the leukocytes by both groups. The most common complica- filtration or washing. These antibodies as tion was acute chest syndrome, which well as those againstArchive serum proteins can occurred in 10 percent of patients. There cause allergic reactions that can be pre- were no significant differences between vented by prophylaxis with an antihista- transfusion regimens and any complication minefor (Benadryl historical®), removal of leukocytes Reference except transfusionOnly complications, which or plasma by washing, or use of other occurred in 14 percent of aggressively measures previously noted. transfused patients and 7 percent of conservatively managed patients. In addition, Infection preoperative hospitalization days attributed to transfusion preparation were 4 days in Hepatitis and other transfusion-transmitted the aggressively transfused patients com- viral diseases in blood occur with the same pared with approximately 2 days in conser- frequency in sickle cell patients as in other vatively managed patients. In conclusion, patients receiving transfusions. The effects present data suggest that routine hemoglo- may be more severe in sickle cell patients bin SS patients undergoing major elective because of the presence of the disease. surgery should be conservatively transfused Patients receiving multiple transfusions as part of their routine management. should be serially monitored for hepatitis C Transfusion with limited phenotypic units and other viral infections; alpha interferon would most likely eliminate the alloimmu- may be useful in the treatment of patients nization observed from E, K, C, and Fya. with chronic hepatitis B and C. Definitive data to recommend no preopera- Posttransfusion human immunodeficiency tive transfusion in sickle cell disease are virus (HIV) infection and AIDS are reported not available. However, the present stan- in sickle cell disease, occurring as late as 5 dard of practice suggests that no preopera- to 8 years after the transfusion with blood tive transfusion is a possible alternative in not known to be from an infected donor. healthy hemoglobin SC patients and for Thus, patients with sickle cell disease who limited surgery in stable hemoglobin SS were transfused before blood products patients. At present, patients having tonsil- were tested for HIV antibodies (1975-85) as lectomies and adenoidectomies should be well as those transfused with today’s “safe” transfused for surgery. blood should be considered for counseling BIBLIOGRAPHY on testing for HIV infection. Ambruso DR, Githens JH, Alcorn R, et al. TRANSFUSION FOR SURGERY Experience with donors matched for minor blood group antigens in patients with sick- A multi-institutional study recently prospec- le cell anemia who are receiving chronic tively compared perioperative complication transfusion therapy. Transfusion rates of sickle cell anemia patients random- 1987;27:94. ized to aggressive transfusion (decrease Hb S below 30 percent) and conservative Bischoff RJ, Williamson A III, Dalali MJ, et transfusion (Hb S approximately 60 per- al. Assessment of the use of transfusion cent, Hb to 10 g/dL). Serious complications therapy perioperatively in patients with

sickle cell hemoglobinopathies. Ann Surg Greenwalt TJ, Zelenski KR. Transfusion 1988;207:434-8. support for haemoglobinopathies. Clin Brittenham GW, CohenArchive AR, McLaren CE, et Haematol 1984;13:151. al. Hepatic iron stores and plasma ferritin Koshy M, Burd L, Wallace D, Moawad A, concentration in patients with sickle cell Baron J. Prophylactic red-cell transfusions anemia andfor thalassemia historical major. Am J Referencein pregnant patients Only with sickle cell dis- Hematol 1993;42:81-5. ease. A randomized cooperative study. N Castro O, Finke-Castro H, Coats D. Engl J Med 1988;319:1447-52. Improved method for automated red cell Mintz PD, Williams ME. Cerebrovascular exchange in sickle cell disease. J Clin accident during a delayed hemolytic trans- Apheresis 1986;3:93-9. fusion reaction in a patient with sickle cell Cohen A. Treatment of transfusional iron anemia. Ann Clin Lab Sci 1986;16:214. overload. Am J Pediatr Hematol Oncol Orlina AR, Sosler SD, Koshy M. Problems 1990;12:4-8. of chronic transfusion in sickle cell disease. Cohen AR, Martin MB, Silber JH, Kim HC, J Clin Apheresis 1991;6:234-40. Ohene-Frempong K, Schwartz E. A modi- Piomelli S. Chronic transfusion in patients fied transfusion program for prevention of with sickle cell disease. Implications and stroke in sickle cell disease. Blood problems. Am J Pediatr Hematol Oncol 1992;79:1657-61. 1985;7:51. Comer GM, Ozick LA, Sachdev RK, et al. Piomelli S, Seaman C, Ackerman K, Blei F. Transfusion-related chronic liver disease in Planning an exchange transfusion in sickle cell anemia. Am J Gastroenterol patients with sickle cell syndromes. Am J 1991;86:1232-4. Pediatr Hematol Oncol 1990;12:268-76. Cox JV, Steane E, Cunningham G, Frenkel Rackoff WR, Ohene-Frempong K, Month S, EP. Risk of alloimmunization and delayed Scott JP, Neahring B, Cohen AR. Neurologic hemolytic transfusion reactions in patients events after partial exchange transfusion for with sickle cell disease. Arch Intern Med priapism in sickle cell disease. J Pediatr 1988;148:2485-9. 1992;120:882-5. Cummins D, Webb G, Shah N, Davies SC. Reisner EG, Kostyu DD, Phillips G, et al. Delayed haemolytic transfusion reactions in Alloantibody responses in multiply trans- patients with sickle cell disease. Postgrad fused sickle cell patients. Tissue Antigens Med J 1991;67:689-91. 1987;30:161. Epps CH Jr, Bryant DD III, Coles MJ, Castro Rosse WF, Gallagher D, Kinney TR, et al. O. Osteomyelitis in patients who have sick- Transfusion and alloimmunization in sickle le cell disease. Diagnosis and management. cell disease. The Cooperative Study of J Bone Joint Surg 1991;73:1281-94. Sickle Cell Disease. Blood 1990;76:1431-7. Fullerton MW, Philippart AI, Sarnaik S, Lusher J. Preoperative exchange transfusion Schmalzer EA, Lee JO, Brown AK, et al. in sickle cell anemia. J Ped Surg Viscosity of mixtures of sickle and normal 1981;16:297-300. red cells at varying hematocrit levels.

Implications for transfusion. Transfusion in sickle cell anemia and transfusion of 1987;27:228. racially unmatched blood. N Engl J Med 1990;322:1617-21. Silliman CC, PetersonArchive VM, Mellman DL, Dixon DJ, Hambidge KM, Lane PA. Iron Vichinsky EP, Haberkern CM, Neumayr L, chelation by deferoxamine in sickle cell et al. A comparison of conservative and patientsfor with historical severe transfusion-induced Referenceaggressive Only transfusion regimens in the peri- hemosiderosis: a randomized, double-blind operative management of sickle cell dis- study of the dose-response relationship. J ease. N Engl J Med 1995;333(4):206-13. Lab Clin Med 1993;122:48-54. Wang WC, Kovnar EH, Tonkin IL, et al. Sosler SD, Jilly BJ, Saporito C, Koshy M. A High risk of recurrent stroke after discon- simple, practical model for reducing alloim- tinuance of five to twelve years of transfu- munization in patients with sickle cell dis- sion therapy in patients with sickle cell disease. Am J Hematol 1993;43:103-6. ease. J Pediatr 1991;118:377-82. Talacki CA, Ballas SK. Modified method of Wayne AS, Kevy SV, Nathan DG. exchange transfusion in sickle cell disease. Transfusion management of sickle cell dis- J Clin Apheresis 1990;5:183-7. ease. Blood 1993;81:1109-23. Vichinsky EP, Earles A, Johnson RA, Hoag MS, Williams A, Lubin B. Alloimmunization

Archive for historical Reference Only

CHAPTER 11 SPLENIC SArchiveEQUESTRATION AND TRANSIENT APLASTIC CRISIS for historical Reference Only

Acute exacerbation of anemia in the patient reaching into the pelvis. The usual clinical with sickle cell disease is a significant cause manifestations of this complication are sud- of morbidity and mortality. The most com- den weakness, pallor of the lips and mon processes leading to these “crises” in mucous membranes, tachycardia, tachyp- the United States are splenic sequestration nea, and abdominal fullness. Anemia can and erythroid aplasia. be profound, thrombocytopenia due to splenic entrapment is common, and the SPLENIC SEQUESTRATION reticulocyte count is often markedly elevated. Splenic sequestration is one of the most Much of the severe morbidity and mortality dangerous events in the life of a patient of sickle cell anemia in the first few years with sickle cell anemia and must be of life is a consequence of the so-called promptly recognized and treated. Within acute splenic sequestration crisis. This was hours of the first signs of this disturbance, first described in 1945 in a review of 11 hypovolemic shock and death can occur. fatal cases of sickle cell anemia where death was caused by “abdominal crises.” With increasing numbers of children diag- These catastrophic events were character- nosed at birth with sickle cell disease and ized by severe anemia, splenomegaly, carefully followed thereafter, it has become hypovolemic shock, and sudden death, and apparent that minor (or “subacute”) it was suggested that patients had literally episodes of splenic sequestration are com- “bled into their spleens.” mon. These episodes are characterized by a moderate increase in spleen size associat- Infants and young children with sickle cell ed with a fall in baseline hemoglobin level anemia whose spleens have not yet under- of 2 to 3 g/dL. The reticulocyte count may gone multiple infarctions and subsequent increase above usual levels. These episodes fibrosis, and those individuals with other may resolve spontaneously or splenomegaly forms of sickle cell disease whose spleens may persist; management consists of care- remain enlarged into adult life, can sudden- ful surveillance. Some patients may ulti- ly have intrasplenic pooling of vast mately require splenectomy if significant amounts of blood. In SS disease, these cytopenias occur. events can occur as early as 2 months of age and are unusual after age 3 years. Early diagnosis of sickle cell disease per- They are often associated with viral or bac- mits training of parents to palpate their terial infections. During severe splenic infants’ abdomens to determine the size of sequestration, the spleen becomes enor- the spleen (see Chapter 1). Parents must mous, filling the abdomen and even be instructed to seek immediate medical

attention if they notice increased pallor, considered if a child has had two or more abdominal pain or enlargement, or rapid of these episodes; some would recommend splenic enlargement. Educating parents is splenectomy after a single severe episode. an essential componentArchive of newborn screen- Because the spleen in SS disease is fre- ing followup and has resulted in reduced quently dysfunctional after 6 to 9 months mortality from splenic sequestration. of age, the risk of postsplenectomy infec- for historical Referencetion is probably Only not greatly increased. Splenic sequestration crises can occur in Alternatively, a program of chronic transfu- older patients with Hb SC disease and Sβ+ sion can be used in infants younger than thal whose spleens either remain enlarged age 2 years, the age at which immunization or retain the capability to enlarge. Although with the pneumococcal vaccine is more these episodes are often mild, are associat- effective. Chronic transfusion therapy usu- ed with decreased hemoglobin levels of 2 ally reduces spleen size, restores function, to 3 g/dL, and rarely require supportive and prevents sequestration, thus avoiding transfusions, severe and fatal sequestration splenectomy in the very young child. has occurred in some patients. When transfusions are discontinued, how- In children or adults with splenomegaly ever, the child may again be at risk for (usually patients with Hb SC disease or sequestration. Educating parents about Hb Sβ+ thal), acute splenic infarction may splenic palpation is particularly important occur, causing severe left upper quadrant after the child has had an initial episode. pain that is sometimes accompanied by a Some patients with sickle cell disease “splenic friction rub” audible when the develop chronic massive splenomegaly patient inspires. The infarcts may be with associated hypersplenism. visualized by CT or MRI scans. Although Splenectomy is indicated when the degree these episodes often resolve with conserva- of anemia, neutropenia, or thrombocytope- tive management, intractable pain may nia is severe, or when pain or discomfort is necessitate splenectomy. associated with the enlarged spleen. Treatment of the acute splenic sequestration is directed toward the prompt correc- TRANSIENT APLASTIC CRISES tion of hypovolemia with plasma Because the red blood cell lifespan is expanders followed by red blood cell shortened in sickle cell disease, even tran- transfusion as they become available. A sient suppression of erythropoiesis can dramatic regression of splenomegaly and result in severe anemia; these episodes are rise in hemoglobin level can occur in a called transient aplastic crises. The large short time after transfusion. Because of this majority of episodes of severe reticulocy- phenomenon, the goal of transfusion topenia are due to infection by parvovirus should be to restore intravascular volume B-19, also the cause of erythema infectio- and achieve a posttransfusion hemoglobin sum (“fifth disease”). Patients may present level of 6-8 g/dL; although transfusion is with increased fatigue, dyspnea, more usually required, care should be taken not severe anemia than usual, and few or no to overtransfuse. Because severe splenic reticulocytes. The anemia is often well- sequestration can result in fatality within a compensated, with minimal elevation of few hours and because of its tendency to pulse or respiratory rate. Although fever recur, splenectomy should be strongly

and signs of upper respiratory infection patient can herald aplastic crisis. Therefore, may be present, skin rash is characteristi- the evaluation of the febrile patient should cally absent. Concurrent acute chest syn- include measurement of the reticulocyte drome may occur.Archive Confirmation of acute count; a low reticulocyte count mandates parvovirus B-19 infection is possible by a further monitoring of the hemoglobin variety of serological and microbiological level. Various viral and bacterial infections techniques.for historical Erythroid aplasia terminates Referencecan cause Only transient and less severe spontaneously after 5 to 10 days; leuko- hypoplasia. Particularly in adolescents and erythroblastosis is common in the peripher- adults, urinary tract or pulmonary infec- al blood during recovery. Patients who tions, as well as severe and protracted present in the convalescent phase may be painful crises, should be considered causes mistakenly assumed to have hyperhemoly- of reticulocytopenia. sis because of severe anemia and high reticulocyte levels. BIBLIOGRAPHY Treatment for transient aplastic crisis is sup- Emond AM, Collis R, Darvill D, et al. Acute portive. Packed red blood cell transfusions splenic sequestration in homozygous sickle are often necessary in those with SS dis- cell disease: natural history and manage- ease and Sβo thal because of tachycardia ment. J Pediatr 1985;107:201. and tachypnea. Transfusions are required less frequently in those with other forms of Kinney TR, Ware RE, Schultz WH, et al. sickle cell disease. If the patient can be Long-term management of splenic seques- relied on to return for frequent checkups tration in children with sickle cell disease. J or seek medical help if symptoms worsen, Pediatr 1990;117:194. prolonged hospitalization is usually not Pattison JR, Jones SE, Hodgson J, et al. required. Parvovirus infections and hypoplastic crises In addition to erythema infectiosum, par- in sickle cell anemia. Lancet 1981;1:644. vovirus B-19 has been associated with Seeler RA, Shwiaki MZ. Acute splenic hydrops fetalis secondary to intrauterine sequestration crises in young children with infection and chronic viremia with anemia sickle cell anemia. Clin Pediatr or pancytopenia in patients with immuno- 1972;11:701. deficiency. Respiratory isolation of patients Serjeant GR, Serjeant BE, Thomas PW, et al. with transient aplastic crisis should be Human parvovirus infection in homozy- implemented to prevent exposure of other gous sickle cell disease. Lancet patients with sickle cell disease, patients 1993;341:1237-40. with immunodeficiency (e.g., congenital, HIV-related, or chemotherapy-induced), Topley AM, Rogers DW, Stevens MCG, et and pregnant females (i.e., nursing staff). al. Acute splenic sequestration and hyper- Patients should be considered infectious splenism in the first five years in homozy- until reticulocytosis occurs. gous sickle cell disease. Arch Dis Child 1981;56:765. A marked decrease in the reticulocyte count below what is usual for a given

Archive for historical Reference Only

CHAPTER 12 EYE Archive for historical Reference Only

Sickle cell hemoglobinopathies have the slight elevation may result in permanent potential to cause ophthalmic complica- loss of vision (see “sickle cell hyphema” tions that affect vision. Unless the ophthal- below). moscopic evaluation includes a thorough examination of the posterior and peripheral NONPROLIFERATIVE SICKLE retina through a dilated pupil, these RETINOPATHY complications can go unnoticed. Nonproliferative sickle retinopathy includes Proliferative sickle retinopathy (PSR) can vascular occlusions, retinal hemorrhages, lead to vitreous hemorrhage and retinal retinoschisis cavities, iridescent spots, black detachment. Laser photocoagulation can sunbursts, angioid streaks, and macular benefit many patients with proliferative changes. These changes usually do not retinopathy. A certain percentage of affect visual acuity. patients who develop retinal holes or traction can be spared retinal detachment and PROLIFERATIVE SICKLE blindness if they are treated appropriately. RETINOPATHY Once detachment or nonclearing vitreous Although peripheral retinal vascular occlu- hemorrhage is present, surgical intervention sions are often observed in childhood, reti- is often helpful in restoring vision. nal neovascularization generally occurs in It is recommended that patients with sickle the second and third decade. Retinal neo- hemoglobinopathies have yearly eye exam- vascularization is most common in Hb SC inations, including indirect ophthalmos- disease but may also be seen in SS disease β copy. These examinations should begin in and S thal. childhood (see Chapter 2, Adult Health The evolution of neovascularization is Care Maintenance). Patients with significant affected by the patient’s age and hemoglo- retinopathy should undergo fluorescein bin type. It remains unclear why neovascu- angiography and be evaluated and fol- larization progresses rapidly in some lowed by a retinal specialist. Immediate patients with sickling hemoglobinopathies referral to an ophthalmologist is also indi- and is virtually absent in others with the cated when there is a sudden change in same hemoglobin type. The risk of further visual acuity or when there is trauma to hemorrhage depends in part on the the eye. Trauma is often associated with amount of neovascularization. Untreated elevated intraocular pressures, and, in a sickle cell retinopathy may cause blindness patient with sickle cell disease, even a by vitreous hemorrhage or retinal detachment.

Laser photocoagulation is often effective in pressure. Moderate elevation of intraocular eradicating proliferative retinopathy with an pressure in eyes of patients with sickle cell acceptably low rate of complications. disease hemoglobinopathy can produce Archivepermanent deterioration of visual function. VITREOUS HEMORRHAGE AND These patients should be referred immedi- RETINALfor DETACHMENT historical Referenceately to an ophthalmologist Only for medical or Proliferative sickle retinopathy causes vitre- surgical intervention. ous hemorrhage. Degeneration and fibrosis of the vitreous cavity can lead to a traction- BIBLIOGRAPHY al detachment of the retina or retinal hole Cohen SB, Fletcher MF, Goldberg MF, formation, sometimes followed by detach- Jednock N. Diagnosis and management of ment. These are the most common causes ocular complications of sickle hemoglo- of blindness in sickle cell disease. If a vitre- binopathies. Ophthalmic Surg Part I ous hemorrhage does not clear in 3 to 6 1986;17(1.6):57-374. months or if a tractional retinal detachment Condon PI, Serjeant GR. Photocoagulation occurs, vitrectomy (removal of the vitre- in proliferative sickle retinopathy: results of ous), often in combination with a retinal a 5-year study. Br J Ophthalmol detachment operation (a scleral buckling 1980;64:832-40. procedure), is the treatment of choice. Partial exchange transfusion (see Chapter Goldberg MF. Classification and pathogene- 10, Transfusion) is recommended for all sis of proliferative sickle retinopathy. Am J patients with sickle hemoglobinopathies Ophthalmol 1971;71:649-65. before eye surgery in an effort to improve Goldberg MF, Jampol LM. Treatment of treatment of potential postoperative com- neovascularization, vitreous hemorrhage, plications such as hyphema and ischemic and retinal detachment in sickle cell necrosis of the anterior segment of the eye. retinopathy. Symposium on medical and surgical diseases of the retina and vitreous: SICKLE CELL HYPHEMA transactions of the New Orleans Academy Individuals with sickle cell hemoglo- of Ophthalmology. St. Louis: CV Mosby, binopathies, including sickle cell trait, who 1983;5:53-81. have hyphemas (blood in the anterior Jampol LM, Condon P, Farber M, Rabb M, chamber) due to trauma or surgery are at Ford S, Serjeant G. A randomized clinical risk of developing elevated intraocular trial of feeder vessel photocoagulation of pressure even if only small amounts of proliferative sickle cell retinopathy. blood are present. The biochemical and Ophthalmology 1983;90:540-5. metabolic conditions in the aqueous humor favor erythrocyte sickling, and as a result, Nagpal KC, Goldberg MF, Rabb MF. Ocular sickle erythrocytes can plug the outflow manifestations of sickle hemoglobinop- pathways and cause increased intraocular athies. Surv Ophthalmol 1977;21:391-411.

CHAPTER 13 CONTRACEPTIONArchive AND PREGNANCY for historical Reference Only

Pregnancy carries some increased risk for a present serious problems for women with woman with sickle cell disease and her sickle cell disease. Condoms are less reli- fetus, but the risks are not so great as to able but also provide protection against the prohibit desired pregnancies. Every woman spread of AIDS and other sexually transmit- of childbearing age with sickle cell disease ted diseases. Adolescents and preteens who is sexually active should be advised of should receive sex education that includes the likelihood that her pregnancies will be a discussion of abstinence. successful but should also be advised that some risks may be greater than for women MANAGEMENT OF PREGNANCY without sickle cell disease. Particular atten- Women should be advised to seek medical tion should be given to ensure that the care early in pregnancy. Prenatal care genetics of sickle cell disease is understood. should be with either the primary physician or the obstetrician; full responsibility CONTRACEPTION should be in one set of hands, with advice Sickle cell disease is not an indication for from the other. An obstetrician or high-risk sterilization. Contraception, however, offers clinic experienced in the management of the option of informed family planning. women with sickle cell disease is best if The methods for contraception include bar- available. Initial assessment should include rier methods, oral contraceptives, long-act- a medical history directed to eliciting fac- ing intramuscular contraceptives, intrauter- tors that influence pregnancy outcome such ine devices (IUDs), and condoms. There is as obstetrical experiences; medical compli- no evidence that use of the pill is more cations such as renal, neurological, or dangerous for women with sickle cell dis- pulmonary difficulties; chemical dependen- ease than for those without the disease. cy (either prescription or other); and exces- Studies in women without sickle cell dis- sive alcohol or tobacco use. Visits should ease have shown that low-dose estrogen include close monitoring and should be oral contraceptives are the most reliable of frequent—ideally, every 2 weeks until the the common contraceptive methods. The 28th week of pregnancy and weekly there- long-acting intramuscular contraceptives are after. All pregnant patients should receive 1 also effective. Barrier methods such as a mg of folic acid daily in addition to the usual diaphragm and gel have a higher rate of prenatal vitamins, minerals, and iron supple- failure than oral contraceptives. The IUDs ments, unless iron stores are known to be are very reliable but cause a significant risk increased. All routine prenatal screening of bleeding and infection that would examinations should be performed.

All patients should be screened for the falls. Stress tests should be used if there are presence of red cell alloantibodies, regard- questions of uteroplacental insufficiency. less of their transfusion history. A patient Although some physicians institute prophy- should be told if antibodiesArchive are present lactic transfusion in asymptomatic pregnant and given a document with details in case patients with SS disease, there is no firm she deliversfor at a historicalhospital other than the Referenceevidence that Onlyoutcomes improve because one planned for delivery. Management of of such transfusions. However, transfusions the alloimmunized mother should follow continue to play an important role in the meticulous prenatal obstetrical practices management of acute events. that include following Rh or other antibody titers, administering Rh immunoglobulin if SICKLE-RELATED COMPLICATIONS indicated, and performing amniocentesis to OF PREGNANCY assess fetal development and bilirubin con- The management of painful episodes does centration. If alloantibodies are identified, not differ during pregnancy (see Chapter 7, arrangements with the blood bank should Painful Events). Narcotics can be used in be made early in pregnancy to identify, if conventional doses, and hydration is possible, sources of compatible blood. important. Other complications of sickle The father should also have his hemoglo- cell disease, including acute chest and right bin type identified. If he has sickle cell trait upper quadrant syndromes, acute anemic or is a carrier of another hemoglobinopa- episodes, new onset neurological events, thy (including thalassemia), the possibility and septicemia, should be managed as they of prenatal diagnosis to identify sickle cell are in nonpregnant patients. Preexisting disease in the fetus should be raised early renal disease and congestive heart failure in pregnancy. Such services are described may worsen during pregnancy. in Chapter 14, Prenatal Diagnosis. Intrauterine growth can be gauged by the COMPLICATIONS OF PREGNANCY measurement of fundal height and con- Intrauterine growth retardation occurs with firmed by ultrasound. The cervix is exam- greater frequency in patients with SS dis- ined in the second and third trimester to ease than in SC disease and Sβ+ thal detect softening and dilatation, which may patients. Preterm labor and premature suggest preterm labor. Monitoring every 2 delivery occur with increased frequency; weeks or weekly after 28 weeks by non- risk factors include severe anemia, stress test, stress test, biophysical profile, increased prostaglandins, abruptio placen- umbilical blood flow, and recording of fetal tae, placenta previa, multiple gestations, well-being by the method of Sadovsky and urinary tract infection, cigarette smoking, Polishuk are useful and cost efficient. As and overuse of narcotics. Toxemia of preg- with any pregnancy in which intrauterine nancy, thrombophlebitis, pyelonephritis, growth retardation becomes evident, and spontaneous abortions may have bedrest is recommended and early delivery increased frequency in patients with sickle considered if growth fails to accelerate cell disease. These should be treated as in toward the normal rate or if urinary estriol the patient who does not have sickle cell disease.

DELIVERY hypertonic urea is safe. At the first followup visit, the patient should be coun- The hemodynamics of anemia and high seled about contraceptive techniques. cardiac output are accentuated during peri- ArchiveRh-negative women should receive Rh ods of uterine contraction. Pain should be immunoglobulin after therapeutic or counteracted by the liberal use of narcotics. spontaneous abortion. If deliveryfor ishistorical uncomplicated, local Reference or Only regional anesthesia is advised. If fetal dis- BIBLIOGRAPHY tress or anatomic considerations prompt cesarean section, general or spinal anesthe- Beischer N. The effect of maternal anemias sia is necessary. Blood loss should be upon the fetus. J Reprod Med 1971;6:21. replaced according to the usual obstetrical Charache S, Scott J, Niebyl J, Bonds D. practice. Cardiac function may be compro- Management of sickle cell disease in preg- mised by hypoxemia, anemia-increased nant patients. Obstet Gynecol 1980;55:407- fluid loss, and acidosis. Transfusion in rela- 10. tion to anesthesia is discussed in Chapter 10. Oxygen and maintenance hydration Chez RA, Mishell DR. Control of human should be administered during labor and reproduction: contraception, sterilization, delivery. and pregnancy termination. In: Scott JR, DiSia P, Hammon CB, Spellacy WN (eds). POSTPARTUM CARE Danforth’s obstetrics and gynecology. Philadelphia: JB Lippincott Co., 1994:622. Routine postpartum care should be followed meticulously, and hydration should Koshy M. Sickle cell disease and preg- be maintained. The risk of embolism can nancy. Blood Reviews 1995;9:157-64. be reduced by the use of embolic stockings Koshy M, Burd L. Management of preg- and early ambulation. Preventing atelectasis nancy in sickle syndromes. In: Nagel R in postpartum patients is important, and (guest ed). Hematology/oncology clinics of fevers should be aggressively diagnosed North America. Philadelphia: WB Saunders and treated. The newborn baby should be & Company, June 1991;5(3):585-96. screened for hemoglobinopathies as well as Koshy M, Burd L, Wallace D, Moawad A, other genetic disorders (see Chapter 5, Baron J. Prophylactic red-cell transfusions Newborn Screening). in pregnant patients with sickle cell dis- INTERRUPTION OF PREGNANCY ease. A randomized cooperative study. N Engl J Med 1988;319:1447-52. If interruption of pregnancy is considered Milner PF, Jones BR, Dobler J. Outcome of at less than 13 weeks, analgesia rather than pregnancy in sickle cell anemia and sickle anesthesia is usually all that is required for cell hemoglobin C disease. Am J Obstet suction curettage. Beyond 13 weeks, hyper- Gynecol 1980;138:239-45. tonic urea solutions are injected into the uterus, and contractions are stimulated with Powars DR, Sandhu M, Niland-Weiss J, prostaglandin F2. Hypertonic sodium chlo- Johnson C, Bruce S, Manning PR. ride solution should not be injected Pregnancy in sickle cell disease. Obstet because it can cause sickling; however, Gynecol 1986;67:217-28.

Rosse WF, Gallagher D, Kinney TR, et al. value at time of delivery. Obstet Gynecol Transfusion and alloimmunization in sickle 1977;50:49. cell disease. Blood 1990;76:1431-7.ArchiveTuck S. Pregnancy in sickle cell disease in Sadovsky E, Polishuk WZ. Fetal movements the UK. Br J Obstet Gynecol 1983;90:112-7. in vitro: nature,for assessment,historical prognostic Reference Only

CHAPTER 14 PRENATALArchiveDIAGNOSIS for historical Reference Only

Each year in the United States there are welfare is never enhanced by prenatal 4,000 to 5,000 pregnancies at risk for sickle diagnosis. Counseling includes an objective cell disease. As with other genetic diseases, description of a patient’s life with a particu- advances in technology have provided safe lar form of sickle cell disease. It is impor- and accurate methods for performing pre- tant that counseling takes into account the natal diagnosis for sickle cell disease as clinical differences among the various types early as the 10th gestational week. Prenatal of sickle cell disease and the heterogeneity diagnosis is best accomplished by a repro- within genotypes. It is also important that ductive genetics team familiar with sickle discussions of prenatal diagnosis and preg- cell disease and experienced in the provi- nancy interruption be conducted in a sensi- sion of accurate genetic diagnosis of cou- tive nondirected manner. Many patients ples at risk after nondirected genetic coun- have relatively benign disease; the ability seling. The team must be expert in obtain- to predict disease severity would be a valu- ing a fetal sample for analysis and perfor- able asset in counseling and prenatal diag- mance of diagnostic laboratory tests and nosis, but this is still lacking. Currently, must be prepared to handle consideration some centers introduce couples at risk to of pregnancy termination. A necessary pro- patients with sickle cell disease to provide viso for prenatal diagnosis of sickle cell a better understanding of the disease and a disease is that diagnostic methodology not firmer basis for decisions on prenatal diag- be allowed to exceed our ability to predict nosis and possible interruption of pregnancy. clinical severity. The degree of control that The decision regarding use of the results of ethically can be exerted over the biological prenatal diagnosis should always be left to makeup of unborn children must be the parents; informed decisionmaking is weighed. their prerogative. Couples who elect to have prenatal diagno- COUNSELING sis must be referred to an appropriate cen- Couples at risk for conceiving a child with ter as early in pregnancy as possible homozygous SS disease, Hb SC disease, or because the time-consuming diagnostic Sβ thalassemia should be referred for processes must be completed before the genetic counseling. This process must be 24th gestational week, after which preg- carried out with the realizations that all nancies for genetic diseases are not mothers requesting prenatal diagnosis terminated. desire to bear children and that fetal

GENETICS erozygosity in homozygous fetuses. CVS is not recommended until after 10 weeks’ Codominant inheritance of the sickle cell gestation, and diagnoses of heterozygosity gene means that individuals homozygous Archivemust be confirmed by amniocentesis later for the mutation have clinical disease and in pregnancy. The use of preimplantation that heterozygous individuals, although testing and assaying fetal cells in the mater- asymptomatic, are detectable. When an for historical Referencenal circulation Only offer hope for safer sam- individual with sickle cell trait is consider- pling in the future. ing conceiving a child with a mate who is heterozygous for Hb S, Hb C, or β thal- The Hb S and Hb C genes can be detected assemia, there is a one-in-four chance for directly in fetal DNA samples. If the specif- each pregnancy that the offspring will ic mutation responsible for thalassemia in a inherit a form of sickle cell disease. When parent is known, that gene can also be one parent has sickle cell anemia and the detected. In some laboratories, several rela- other is heterozygous for any of these three tively common mutations are sought, but a disorders, there is a one-in-two chance negative result is not helpful. The use of with each pregnancy of conceiving a child genetic linkage analysis for indirect identifi- with sickle cell disease. cation of these genes is no longer necessary. Fetal blood sampling is used only in FETAL TISSUE SAMPLING centers where DNA-based testing is unavailable. Analyses are performed on DNA from fetal cells obtained by chorionic villus sampling DIAGNOSTIC TESTS (CVS) in the first trimester, perhaps as early as the 10th gestational week. As an alterna- Tests using polymerase chain reaction tive approach, amniocentesis can be per- (PCR) provide sensitivity, simplicity, and formed safely in the l6th gestational week, rapidity to DNA-based methods. PCR pro- a time when there is sufficient amniotic vides greater amounts of DNA for analysis, fluid. These sampling methods result in a often obviates the wait for tissue culture far lower rate of fetal demise than the fetal growth, and shortens the time for diagnosis blood sampling method practiced previous- to days rather than weeks. Several molecu- ly, and their use now is nearly universal. It lar diagnostic laboratories are available is common practice to initiate tissue culture with expertise in prenatal diagnosis of as a backup source of fetal DNA in case hemoglobinopathies. insufficient DNA for analysis is obtained initially. The emphasis on methods of early BIBLIOGRAPHY sampling to safeguard against unacceptable Driscoll MC, Lerner N, Anyane-Yeboa K, delays in diagnostic testing have encour- et al. Prenatal diagnosis of sickle hemoglo- aged the use of CVS as the method of binopathies: the experience of the choice for fetal sampling. However, the use Columbia University Comprehensive Center of CVS before 9 weeks’ gestation is associ- for Sickle Cell Disease. Am J Hum Genet ated with increased rates of limb reduction 1987;40:548-58. anomalies. Moreover, when CVS is used for sampling, confined placental mosaicism Embury SH. Prenatal diagnosis. In: Embury may result in mistaken diagnoses of het- SH, Hebbel RP, Mohandas SN, Steinberg

MH (eds). Sickle cell disease: basic princi- Filkins K, Russo JF (eds). Human prenatal ples and clinical practice. New York: Raven diagnosis. 2nd ed. New York: Marcel Press, 1994:485-503.ArchiveDekker, 1990:1-601. Evans MI, Johnson MP (eds). Prenatal diag- Goldberg JD (ed). Fetal medicine. West J nosis in the 90’s. J Reprod Med 1992;37:387- Med 1993;159:259-407. 444.for historical ReferencePowledge Only TM, Fletcher J. Guidelines for Evans MI, Thomson EJ, Rothenberg K. the ethical, social and legal issues in prena- Reproductive genetic testing: impact upon tal diagnosis. N Engl J Med 1979;300:168-72. women. Fetal Diagn Ther 1993;8(suppl 1):1-246.

Archive for historical Reference Only

CHAPTER 15 GALLBLADDERArchive AND LIVER for historical Reference Only

GALLBLADDER Differential Diagnosis Gallstones can be totally asymptomatic for Pathophysiology many years. Alternatively, they may cause Because red blood cell hemolysis increases chronic symptoms of fullness after meals, bilirubin production, the total serum biliru- nausea, vomiting, and right upper quadrant bin is increased in hemolytic diseases. This pain. Complications of cholelithiasis is accentuated in sickle cell disease include acute cholecystitis, common bile because red blood cell sequestration in the duct obstruction, and acute pancreatitis. liver and consequent hepatocellular dys- Biliary colic may cause right upper quad- function cause decreased bilirubin excre- rant or diffuse abdominal pain. This tion. The increase in bilirubin is typically abdominal pain may also be due to peptic most marked in SS disease and Sβo thal, is ulcer disease in patients with SS disease less likely in hemoglobin SC disease, and and should be considered in the history may be absent or only slightly increased in and, if indicated, evaluated by examination Sβ+ thal. When the liver is functioning at of the upper gastrointestinal tract. Although maximum efficiency, the total serum biliru- gallstones are often seen on the plain radi- bin should not exceed 4 mg/dL, and the ograph, a biliary ultrasound investigation conjugated fraction should not exceed 10 not only detects stones more accurately but percent of the total. can also detect biliary sludge (the precur- Because of the increase in bilirubin pro- sor of stones), a deformed or thickened duction, gallstones are common in SS dis- gallbladder wall, and changes in the caliber ease. They are found in approximately 14 of the common bile duct. Ultrasound also percent of children younger than age 10 provides information about the liver and years, about 30 percent of adolescents, and pancreas and saves the patient multiple about 75 percent of adults by age 30 years. x-ray exposures associated with contrast Gallstones are almost as common in Sβo cholecystography. Scanning after the thal and also occur in about 40 percent of administration of technetium-99m iminodi- patients with Hb SC disease and 20 percent acetic acid (HIDA) is particularly useful to of patients with Sβ+ thal. Gallstones are fre- confirm cystic duct occlusion and to evalu- quently multiple. They are composed main- ate gallbladder function (after the adminis- ly of desiccated bile, which is radiolucent, tration of cholecystokinin). Newer analogues but the stones are radiopaque and contain (mebrofenin, for example) can be used at calcium bilirubinate in about 60 percent of higher serum bilirubin concentrations than patients. HIDA.

Management Preparation for Cholecystectomy In most patients, management does not dif- The question of whether preoperative fer from that used inArchive the general popula- transfusion is necessary before major tion. Most physicians defer surgery until abdominal surgery is discussed in Chapter symptoms occur. However, some physi- 10, Transfusion. Currently, most patients cians recommendfor historical cholecystectomy once Referenceundergoing laparoscopic Only cholecystectomy stones are identified because of frequent are not transfused preoperatively if their difficulty in diagnosing the cause of hemoglobin level is above 7.0 g/dL. As for abdominal pain in children with sickle cell all patients, anesthesia for sickle cell dis- disease. In adult patients, vague right ease patients requires maintenance of good upper quadrant discomfort after meals can hydration, normal body temperature, and be relieved by antispasmodics. Some effective ventilation (see Chapter 21, patients remain symptom free for many Surgery and Anesthesia). An intraoperative years by avoiding dietary excesses and cholangiogram is recommended to rule out restricting their intake of fried and fatty intrahepatic or common duct stones. food. When gallstone symptoms are chronic or recurrent, elective cholecystectomy is Postoperative Care indicated. Right upper quadrant pain is not Postoperative complications may be more relieved by surgery in all patients. common in sickle cell anemia patients than Acute cholecystitis should be treated con- in the general population and include servatively with antibiotics and hydration; atelectasis, pneumonitis, and pulmonary electrolyte balance and general supportive infarction. Preoperative and postoperative measures should be maintained. Elective physiotherapy using an incentive spirome- cholecystectomy should be performed after ter, plus early ambulation, may reduce the the acute attack subsides to avoid adhe- frequency of these complications. Most sions around the inflamed gallbladder (usu- patients have an uneventful recovery from ally within 6 weeks). Emergency surgery surgery. There is no evidence that surgical should be avoided, unless there is evidence wound healing is delayed in patients with of common bile duct obstruction. If sickle cell disease. obstruction is suspected or if liver function tests are significantly more abnormal than ACUTE LIVER DISEASE before the attack, endoscopic retrograde The patient who presents with right upper cholangiography (ERCP) may be quite quadrant abdominal pain, increased jaun- helpful and, occasionally, therapeutic. For dice, and fever needs careful evaluation elective procedures, laparoscopic surgery, and management. The symptoms may be done by experienced providers, has been caused by acute cholecystitis, viral hepati- safe and convenient and has been associat- tis, intrahepatic vaso-occlusive common ed with low postoperative morbidity. Both bile duct obstruction, or drug-induced ERCP and laparoscopic cholecystectomy hepatotoxicity. Episodes of hyperbilirubine- may be necessary if common duct and mia may occur in the absence of abdomi- gallbladder stones are present. nal pain or other symptoms and may have

a benign self-limited course resolving in 1 cause intrahepatic hypoxia, may not be as to 2 weeks. In other cases, liver dysfunc- important a cause of chronic liver dysfunction is associated with fever, leukocytosis, tion as previously thought. In the older and a clinical Archivepresentation similar to that patient, chronic congestive heart failure, seen in drug-induced cholestasis. especially when associated with pulmonary hypertension, may be an important addi- In children and adults, the liver may be the for historical Referencetional factor Only in producing cirrhosis. Careful site of red blood cell sequestration during a evaluation of patients with hepatic compli- vaso-occlusive crisis, with increased jaun- cations, including judicious use of liver dice, an acutely enlarged tender liver, and biopsy, has shown that a substantial pro- a fall in hemoglobin and hematocrit. Acute portion can be explained by disorders liver disease rarely progresses rapidly to unrelated to sickle cell disease. Chronic liver failure with an increase in serum lev- active hepatitis seen on biopsy may be due els of hepatic enzymes, multiple coagula- to the hepatitis B or C virus; if that diagno- tion defects, uncontrollable hemorrhage, sis is confirmed by measurement of anti- and death. body titers or detection of the viral genome Increased levels of serum alkaline phos- by use of PCR, therapy with interferon phatase, lactic dehydrogenase, and SGOT should be considered. (AST) do not necessarily indicate liver disease because they may arise from bone BIBLIOGRAPHY and/or hemolyzed red blood cells. Intermittent elevations of serum liver American College of Physicians. Guidelines enzymes may be seen in the absence of for the treatment of gallstones. Am Intern symptoms, but in acutely ill patients, viral Med 1993;119:620-2. hepatitis should be considered. These Bauer TW, Moore GW, Hutchins GM. The patients may become deeply jaundiced and liver in sickle cell disease. Am J Med show marked abnormalities of serum 1980;69:833-7. aminotransferases and coagulation function Buchanan GR, Glader BE. Benign course of tests. These patients also should be treated extreme hyperbilirubinemia in sickle cell like other patients with liver failure. anemia: analysis of six cases. J Pediatr 1977;91:21-4. CHRONIC LIVER DISEASE Cunningham JJ, Houlihan SM, Altay C. Transfused patients are at risk for viral Cholecystosonography in children with hepatitis, and some will develop chronic sickle cell disease. J Clin Ultrasound active hepatitis and progress to cirrhosis. In 1981;9:231-5. the chronically transfused patient, liver enlargement and fibrosis may result from Hoofnagle JH. Therapy of acute and chron- hemosiderosis, but the incidence of frank ic viral hepatitis. Adv Intern Med hemochromatosis is lower than in thal- 1994;39:241-75. assemia major. Studies of liver biopsy mate- Johnson CS, Omatha M, Tong MV, et al. rials suggest that continued hemolysis and Liver involvement in sickle cell disease. Kupffer cells engorgement, which could Medicine (Baltimore) 1985;64:349-56.

Rosenblate HJ, Eisenstein R, Holmes AW. Sheehy TW, Law DE, Wade BH. Exchange The liver in sickle cell anemia. Arch Pathol transfusion for sickle cell intrahepatic 1980;90:235. Archivecholestasis. Arch Intern Med 1980;140:1364-6. Ransohoff DF, Gracie WA. Treatment of Shubert TT. Hepatobiliary system in sickle gallstones. Am Intern Med 1993;119:606-19. cell disease. Gastroenterology 1986;90:2013- for historical Reference21. Only

CHAPTER 16 LEG ULCERSArchive for historical Reference Only

Between 10 and 20 percent of patients with DIAGNOSIS AND LABORATORY SS disease develop debilitating leg ulcers. TESTS The ulcers usually appear between the A general physical examination should ages of 10 and 50 years and are seen more search for other causes of leg ulcers such frequently in males than in females. Leg as varicose veins, diabetes mellitus, and ulcers are rare in individuals with Hb SC collagen vascular disease. Before therapy, a β disease and S thal as well as in patients radiograph of the leg is needed to establish younger than age 10 years. the presence or absence of chronic changes in the underlying bone. Periosteal PATHOPHYSIOLOGY thickening below the ulcer is not uncom- Sickle cell ulcers usually begin as small, mon, but underlying osteomyelitis is rare. elevated, crusting sores on the lower third Quantitative cultures can be taken from the of the leg, above the ankle and over and base of the ulcer with the use of a dermal around the medial or lateral malleolus. punch biopsy. The aim of treatment is to Occasionally, ulcers are seen over the tibial reduce the colony count by local cleansing area or the dorsum of the foot. They can or topical antibiotics. be single or multiple. Some heal rapidly, others persist for years, and others heal SUGGESTED TREATMENT only to recur in the area of scarred tissue. Leg ulcers are very difficult to treat. There In the early phase, the neighboring skin are many treatment modalities described. appears to be healthy, but as the ulcer None of them has been proved to give persists, the surrounding skin shows hyper- consistently beneficial results. Active pigmentation with a loss of subcutaneous patient participation in the care of leg fat and hair follicles. These ulcers can be ulcers is essential because of the ulcers’ very painful and often are accompanied by chronicity. Nursing staff members can be reactive cellulitis and regional (inguinal) particularly helpful in assisting patients. adenitis. Warmer temperatures, lower Patients should be encouraged to wash steady-state hemoglobin, and lower fetal their legs and feet daily and to wear proper hemoglobin appear to enhance ulcer for- shoes and support stockings. Leg ulcer mation. Once an ulcer forms, recurrence is management is difficult and can be frustrat- common. ing to both patient and medical and nursing

staff members because therapy is often Unna’s Boot (Zinc Oxide- unsatisfactory. Patients should be encour- Impregnated Bandage) aged to promptly report to the physician If healing fails to occur and the ulcer is not when they develop Archivean ulcer. Ulcers less acutely infected, 2 to 3 weeks of Unna’s than 2-3 cm have a greater chance of heal- boot application is recommended. The zinc ing. Once ulcers are persistent for more oxide-impregnated bandage should be than 6 months,for theyhistorical become chronic, andReference Only applied after cleansing (as previously treatment is difficult. described) to cover the ankle, the ulcer area, and up to about 3 inches below the Ulcer Care knee joint. The boot should be left in place ■ Wash the leg with mild soap or diluted for 1 week. It provides support, protects solutions of liquid household bleach (1 the ulcer from trauma, and contributes to tablespoon in 1 gallon of water). Then effective débridement on removal. Three or gently use gauze or a cotton swab to four applications may be required before remove slough from the ulcer base. there is definite evidence of healing, at which time the use of saline dressings can ■ Wet-to-dry dressings will help debride necrotic tissue to achieve a clean(er) be continued. Antibiotics or other ointments base. The dressing is applied after soak- should not be applied under the Unna’s ing it in saline (or diluted household boot bandage because they may react with vinegar if a Pseudomonas infection is zinc to produce an allergic reaction. suspected) and allowed to dry on the ä ulcer. It is then removed (without moist- RGD Peptide Matrix (Argidene Gel ) ening if possible) to debride the ulcer, A topical viscous gel can enhance healing, and the process is repeated at intervals providing the extracellular matrix for physi- of 3 to 4 hours. Rest and elevation of the cal support, the macromolecular scaffold to leg are desirable. facilitate the migration of fibroblasts, and ■ Alternately, the patient can be instructed endothelial cells and keratinocytes to the to have complete bedrest for 7 to 10 wound sites. The gel is applied to cover days. During the day, wet saline dress- the wound once a week, and an Unna ings are applied frequently. At night, dry boot is applied. The procedure is repeated nonstick adhesive dressing is applied until healing begins. and the leg is wrapped with Kerlix dressing. Transfusions ■ Apply cocoa butter or oil over the skin Blood transfusions can be used when the around the ulcer and massage. ulcer does not heal or it progresses with ■ Apply topical antibiotics or antibacterial persistent hyperpigmentation and indura- agents to help reduce local infections tion of the surrounding skin. Transfusions and to enhance the development of should be given to raise the hemoglobin to granulation tissue. Once granulation tis- at least 10 g/dL and to reduce Hb S to less sue appears, saline dressings can be than 30 percent. If the ulcer does not heal used and healing slowly ensues. after 6 months, transfusions should be

discontinued. If healing does occur, trans- should protect the free flap area with prop- fusions should be gradually discontinued. er shoes such as soft boots to avoid scratching the area. The area around the Archiveflap should be well lubricated with baby Skin Grafts oil and massaged at least once a day. Skin grafts may be tried for nonhealing recalcitrantfor historicalleg ulcers and for the patientReferenceCONCLUSIONS Only who does not comply with prolonged medical management. Before plastic surgery, it is If the patient is unwilling to wait the long necessary to reduce the colony count of periods required for the trials of medical bacteria in the ulcer base to less than 105/g treatment, skin grafting may be the proce- of tissue by both débridement and the use dure of choice for chronic ulcers. If a of local antibiotics. breakdown of the graft occurs, a repeat procedure is encouraged. When ulcers The patient should be hospitalized and heal, the scarred tissue is easily injured. prepared for anesthesia with transfusions Foot exercise and elevation of the foot are (see Chapter 10, Transfusion). Skin grafting important to improve circulation. can be performed under general or spinal Continued cooperation among the patient, anesthesia. A split thickness graft from the the surgeon, and the primary physician is thigh area is recommended. The leg should necessary for successful results. be immobilized. The patient may be hospitalized for 1 to 2 weeks following surgery. BIBLIOGRAPHY Hall MG. Progress in the management of Free Flaps (Free Tissue Transfer) leg ulcers in sickle cell disease. In: Scott R Free flaps can be used for patients with (ed). Advances in the pathophysiology, chronic leg ulcers that persist for several diagnosis, and treatment of sickle cell dis- years. With the advent of microsurgery, ease. New York: Alan R. Liss, Inc., 1982;83- free flap grafts may become the procedure 9. of choice for providing sufficient soft tissue Hallbook T, Lanner E. Serum-zinc and heal- for coverage of large recalcitrant ulcers. ing of venous leg ulcers. Lancet 1972;2:780- Flaps include the use of latissimus dorsi 2. muscle, temporoparietal fascia, and split omentum. Koshy M, Entsuah R, Koranda A, et al. Leg ulcers in patients with sickle cell disease. These procedures are a method of primary Blood 1989;74:1403. treatment. Patients need meticulous preoperative preparation, aggressive blood Thompson N, Ell PJ. Dermal overgrafting in transfusion, and continued transfusion in the treatment of venous stasis ulcers. Plast the postoperative period of 3 to 4 months Reconstr Surg 1974;54:290-9. to maintain Hb S at less than 30 percent. In Weinzweig N, Schuler J, Marschall M, et al. the postoperative period, the leg should be Lower limb salvage by microvascular free protected from external trauma and edema. tissue transfer in patients with homozygous Leg elevation, bedrest, and the use of elas- sickle cell disease. Plast Reconstr Surg, in tic stockings are encouraged. The patient press.

Wethers D, Ramirez G, Koshy M, et al. Wolfort FG, Krizek TJ. Skin ulceration in Accelerated healing of chronic sickle cell sickle cell anemia. Plast Reconstr Surg leg ulcers treated with RGD peptide matrix. 1969;43:71-7. Blood 1994;84(Nov Archive6):1775-9. for historical Reference Only

CHAPTER 17 BONES ANDArchiveJOINTS for historical Reference Only

The bones and joints are frequently nutrient artery that penetrate the inner lay- involved in sickle cell disease and are the ers of bone to anastomose with vessels that major sites of pain in vaso-occlusive crises. form the periosteum, infarction frequently Bone marrow hyperplasia occurs as a result causes swelling and edema in the overlying of chronic hemolytic anemia, which can soft tissues. This can mimic acute cause bone distortion in childhood, leading osteomyelitis. The earliest example of this to such deformities as tower skull, bossing is the hand-foot syndrome in infants that is of the forehead, and gnathopathy (distor- discussed later in this chapter. Multiple tion of the maxilla resulting in protrusion long-bone infarcts occur frequently in sick- of the upper incisors and overlapping of le cell crises in older children and adults the upper jaw). Probably because the and can be demonstrated by bone scans. hyperplastic marrow is more vascular than When long-bone infarcts heal, they can fatty, bone marrow infarction is more com- cause new layers of bone to be laid down mon in SS disease than in other forms of in the central cavity, which in radiographs sickle cell disease. give the appearance of “a bone within a bone.” Most patients with SS disease show In cancellous bones such as the vertebrae, these changes. An approach to manage- infarction of bone trabeculae in the central ment of a patient with pain in a long bone part of the vertebral body, supplied by the is outlined (see Chapter 7, Painful Events). nutrient artery, causes a collapse of the vertebral plates leading to compression and Perhaps the most difficult problem caused the classical radiographic appearance of by acute pain and swelling of a long bone “fish mouth” disc spaces and the “step” in sickle cell disease is the differential diag- sign (a depression in the central part of the nosis from acute osteomyelitis. Although vertebral body). Back pain, a common uncommon, infection must always be con- symptom in sickle cell disease, probably sidered, but it can usually be ruled out by indicates a continuation of this process. close clinical observation, blood cultures, Occasionally, other cancellous bones are and occasionally, aspiration of the affected involved such as the metaphysis and epi- area (see Chapter 6, Infection). Plain radi- physis of long bones involving the adjacent ographs are not helpful in the early stages joint, the os calcis causing pain in the heel, and should not be taken routinely. Bone and the bones of the face with resulting scans are not usually helpful in differentiat- pain and swelling. ing a simple infarct from osteomyelitis. In the long bones, because of the anatomic arrangement of the fine branches of the

OSTEONECROSIS OF THE AP and “frog leg” positions and examined FEMORAL AND HUMERAL HEADS for evidence of changes in the bone densi- (ASEPTIC NECROSIS) ty of the femoral head. In the early stages, Archivehowever, the radiographs may appear nor- This condition affects patients with all mal. The earliest changes associated with types of sickle cell disease. The hips and pain can be detected by MRI and radionu- shoulder joints are about equally affected, for historical Referenceclide imaging. Only If there is bilateral disease, although weight bearing makes femoral however, the radionuclide scans may be head necrosis more likely to cause severe difficult to interpret. MRI is very sensitive disability. Although osteonecrosis can occur and can detect small areas of necrosis sev- at any age (the earliest reported case was eral months before symptoms occur; it fre- in a child age 3 years), a recent prospec- quently reveals bilateral disease when tive study of a large number of patients by symptoms are still unilateral. the Cooperative Study of Sickle Cell Disease showed a peak incidence in Hb SS Total hip replacement has no place in the patients between ages 25 and 35 years and management of early osteonecrosis. at a slightly older age in patients with Hb Presently, initial treatment consists mainly SC disease and Sβ+ thal. The natural history of avoidance of weight bearing and judi- of osteonecrosis in sickle cell disease has cious use of local heat and analgesics for yet to be studied in a prospective fashion; pain relief up to 6 months. This is particu- it is clear that when the disease occurs larly important in children and teenagers before closure of the epiphyses, consider- for whom a considerable healing potential able healing can occur. However, patients exists. In children, osteotomy with rotation in their late teens and early twenties pre- to change the area of the head subjected to senting with the early development of a weight has been used in the past with vari- crescent sign (a fracture line within the able results. For older patients with persis- necrotic femoral head beneath the carti- tent hip pain and a positive MRI but with- lage) may have total collapse and destruc- out radiological evidence of collapse, core tion of the head, with persistent pain and decompression of the femoral head per- difficulty in walking within a few months. formed by an orthopedic surgeon experi- In older patients, sclerosis and even some enced in this technique can sometimes considerable deformity of the femoral head result in immediate pain relief. apparent on the radiograph may persist For an individual beyond adolescence who with little change for many years without is severely incapacitated by hip pain and causing much discomfort or disability. who cannot carry out activities of daily life The diagnosis of aseptic necrosis of the and requires relief, surgical replacement of femoral head is usually made when the the entire joint must be considered, even patient complains of intermittent or persis- when the patient is in his or her early tent pain in the groin or buttock. twenties. The patient should be made Occasionally, there may be an acute syn- aware that hip replacement is not always ovitis mimicking a septic arthritis. Any successful in eliminating symptoms and in attempt to move the joint through its range restoring function in sickle cell disease of movement is resisted because of acute patients; also, loosening and other compli- pain. Radiographs should be taken in the cations may necessitate revision (removal

and insertion of a new prostheses) at a in 2 to 3 days, the patient should be evalu- later date. Infection is uncommon, but if ated for osteomyelitis with appropriate removal of the prosthesis later becomes blood cultures and direct aspiration of the necessary becauseArchive of infection, reinsertion area involved. is unlikely to be successful and is rarely considered. OTHER BONE AND JOINT for historical ReferenceSYNDROMES Only Aseptic necrosis of the shoulder may be quite disabling, especially in a person who The differential diagnosis of joint effusions needs to use both arms continuously at in patients with sickle cell disease is diffi- work. Although most painful shoulders set- cult because of a variety of possible etiolo- tle down with NSAIDs, surgical intervention gies. Effusions and periarticular swelling is occasionally warranted and can result can occur secondary to synovial infarction in pain relief and improved range of or infarction in the end of the adjacent movement. long bone. The knee is a common site. Gout, septic arthritis, osteoarthritis, or HAND-FOOT SYNDROME rheumatic or collagen vascular disease The hand-foot syndrome is a fairly com- should be considered and ruled out by mon phenomenon that is seen almost appropriate tests. Because treatments for exclusively in the infant and young child. It these disorders differ, it is important to presents with pain, low-grade fever, and aspirate the joint for culture, protein, and diffuse nonpitting edema of the dorsum of microscopic analysis if the patient is febrile the hands and feet, which extends to the or there are signs of marked inflammation. fingers and toes. One to four extremities Such a tap should be performed in the may be affected at one time. hospital by an experienced physician. If evidence for a coexistent disease is Radiographic changes of elevation of the obtained, it should be treated as in other periosteum and necrosis are seen in the patients. metacarpals and phalanges or metatarsals but may not appear for 1 week or more. In the absence of clear diagnostic findings The syndrome is best treated with analge- (bacteria or uric acid crystals), simple sup- sia, hydration, and parental reassurance. In portive measures, including analgesia, local spite of the often striking radiographic heat, hydration, and bedrest for 5 to 7 changes and swelling that may persist for days, are indicated. NSAIDs are often very several weeks, the syndrome is almost effective for 4 to 6 days and may be tried always self-limited, and bones usually heal in teenagers or adults with normal renal without permanent deformity. Transfusions, function. Other anti-inflammatory agents antibiotics, and other measures are not may also be useful, but proper precautions necessary, but it should be noted that early should be taken to avoid gastric irritation. osteomyelitis can have a similar presenta- If signs of effusion persist, radiographic tion. Therefore, it is recommended that in studies should be obtained, and joint fluid the presence of fever and marked inflamma- analysis may have to be repeated. tion, or if there is no clinical improvement

BIBLIOGRAPHY Mohandes N, Steinberg M. Sickle cell disease. New York: Raven Press, 1994:645-61. Bohrer SP. Bone ischemia and infarction in sickle cell disease. St.Archive Louis: Warren H. Milner PF, Kraus AP, Sebes JI, et al. Sickle Green Inc., 1981. cell disease as a cause of osteonecrosis of the femoral head. N Engl J Med Gaston MH. Sickle cell disease: an 1991;325:1476-81. overview.for Semin historical Roentgenol 1987;22:150-9. Reference Only Milner PF, Kraus AP, Sebes JI, Sleeper LA, Milner PF, Brown M. Bone marrow infarc- et al. Osteonecrosis of the humeral head in tion in sickle cell anemia; correlation with sickle cell disease. Clin Orthop hematologic profiles. Blood 1982;60:1411-8. 1993;289:136-43. Milner PF, Joe C, Burke GJ. Bone and joint disease. In: Embury SH, Hebbel RP,

CHAPTER 18 RENAL Archive for historical Reference Only

Clinical and pathologic data indicate that ml/day—in effect, a form of nephrogenic intravascular sickling occurs more readily diabetes insipidus. The resultant increased in the kidney than in any other organ. A fluid requirement renders the patient much series of progressive and random patholog- more susceptible than the normal individ- ic events involving the kidney begins early ual to dehydration, which is a precipitating in the first decade of life in a patient with cause of vaso-occlusive crises. A liberal sickle cell disease and continues through- fluid intake should be ensured, to provide out life. The distribution of blood flow in for both the obligatory urinary water loss the kidney and the hypertonicity of the and normal daily fluid requirement. The renal medulla create a situation where red abnormality of the renal medulla may ren- blood cells containing sickle hemoglobin der the patient hyporesponsive to “loop” or undergo deoxygenation in an acidic and osmotic diuretic agents such as furosemide hyperosmolar environment that causes or mannitol, respectively. Hyposthenuria them to sickle more easily. The combina- also frequently gives rise to nocturia tion of hypoxia, hypertonicity, and acidosis (enuresis in the child). When the latter in the renal medulla leads to stasis in the occurs, other causes should also be consid- vasa recta and to ischemia of the renal ered. Hyposthenuria is also seen in individ- medulla and papillary tip. Distortion of uals with Hb AS (see Chapter 22, Sickle regional blood flow, focal interstitial Cell Trait.) nephritis and fibrosis, tubular dysfunction and atrophy, and papillary necrosis result. RENAL TUBULAR DYSFUNCTION Table 4 indicates the progressive renal Patients with sickle cell disease are unable events that can occur in each decade of life to acidify their urine maximally when they in association with sickle cell disease. are subjected to acid loading, and this can sometimes lead to significant systemic aci- HYPOSTHENURIA dosis. If metabolic acidosis is found in a The earliest and most common renal defect patient with sickle cell disease, renal in sickle cell disease is hyposthenuria, hydrogen ion excretion should be evaluat- which is expressed as an inability of the ed to determine whether it plays a role in kidney to maximally concentrate the urine. the process. If it is present, it should be It is almost universally evident by the time corrected by judicious therapy with sodium the patient with SS disease reaches age 3 bicarbonate. Impaired renal tubular potassi- years. This condition results in an obliga- um excretion has also been described in tory urinary output of greater than 2,000 sickle cell disease and, in some cases, can

Table 4 Progressive Renal EventsArchive in Sickle Cell Disease First Decade Second Decade Decreased medullary blood flow Microscopic papillary necrosis forNocturia historical Reference Loss of Onlyvasa recta Enuresis Renal tubular siderosis Hyposthenuria Renal tubular acidosis Irreversible hyposthenuria Hyperfiltration Potassium excretion defect Proteinuria Bacteruria Hematuria

Third Decade Fourth Decade and Beyond Macroscopic papillary necrosis Renal failure Interstitial nephritis Membranoproliferative glomerulonephritis Decreased renal blood flow, glomerular filtration rate (GFR) Nephrotic syndrome Pyelonephritis Decreased urate clearance Hypertension

SOURCE: Thompson A, Lessin L, Antonovych T. The sickle cell nephropathies. In: Fried W (ed). Comparative clinical aspects of sickle cell disease. New York: Elsevier, 1982. result in a tendency toward modest hyper- This condition is due to the increase in kalemia, which is hyporesponsive to kali- urate production associated with accelerat- uretic agents such as furosemide. ed erythropoiesis coupled with a decreased Hyperkalemia can increase as patients age. renal clearance of urate. Hyperuricemia in When the amount is significant (K ≥ 5.5 SS disease responds poorly to uricosuric meq), other causes should be sought. agents, but the uric acid level can be low- Spurious hyperkalemia may result from ered with the use of allopurinol. Uric acid hemolysis and/or thrombocytosis. nephropathy is rare, but if recurrent uric acid stone formation occurs, urinary alka- HYPERURICEMIA linization with oral sodium bicarbonate is recommended. Clinical gout is uncommon About 15 percent of children and 40 per- in sickle cell disease. When it is demon- cent of adults with SS disease have high- strated by the presence of intracellular uric normal or elevated serum uric acid levels.

acid crystals in joint fluid, it is treated with should be hospitalized and placed at NSAIDs and allopurinol. bedrest, and high urine flow (> 3 ml/kg/hr) should be maintained. Ferrous sulfate GROSS HEMATURIAArchiveshould be given to correct documented iron deficiency. Gross hematuria occurs commonly in sickle cellfor disease. historical Less commonly, it also Reference occurs Transfusion Only can be indicated both for a in sickle cell trait (although the larger num- falling hematocrit and for reducing the ber of AS persons make them more fre- propensity for occlusion of the medullary quent visitors to medical facilities). The vessels. When hematuria is chronic and bleeding is usually painless, although clot severe, patients should have bedrest with formation in the renal pelvis or ureter can high fluid intake, and exchange transfusion produce renal colic. It is frequently unilat- should be considered with or without eral, with the left kidney being involved in EACA therapy. Every measure should be 80 percent of the cases. It can show a pat- taken to avoid nephrectomy for hematuria tern of intermittency, lowgrade chronicity, in patients with sickling disorders because or persistence. The pathogenic mechanism the contralateral kidney remains at risk for is thought to be sickling in the vasa recta, sickle cell-related complications. Nephrec- which leads to stasis and ischemia, with tomy is warranted only for a life-threatening extravasation of blood into the renal exsanguinating hemorrhage. parenchyma and collecting system, or in some cases to micropapillary or macropap- RENAL PAPILLARY NECROSIS illary necrosis. As with all patients who Renal papillary necrosis is a relatively have hematuria, the differential diagnosis in common finding in patients with sickle cell patients with sickle cell disease includes disease. It can be asymptomatic or accom- papillary necrosis, glomerulonephritis, panied by hematuria or proteinuria. Irregu- tuberculosis, tumor, stones, and urinary larities or “pseudodiverticuli” of the renal tract infection. Bleeding disorders should papillary tips seen on intravenous pyelo- also be considered. Evaluation can require grams (IVP) have been reported in about renal ultrasonography, intravenous pyelog- 50 percent of adults with sickling disorders. raphy (with adequate prehydration), cys- The etiology is identical to that described toscopy, urine culture, and measurements of coagulation and hemostatic function. for hematuria. The disorder is usually asymptomatic and is most commonly Good hydration should be maintained with diagnosed at the time of an IVP. It is a urine flow in excess of 2 to 3 ml/kg/hr to believed that the ischemia or necrosis of decrease the tendency to clot in the renal the renal papillary tip as well as the associ- pelvis and ureter. In the presence of refrac- ated interstitial nephritis, which can also be tory hematuria, patients should be treated caused by heavy ingestion of certain anal- with epsilon aminocaproic acid (EACA) at gesics (e.g., aspirin, acetaminophen, and an oral dosage of 2 to 8 g/day. The princi- NSAIDs ), may cause increased susceptibili- pal danger of this therapy is the formation ty of patients with sickle cell disease to of clots in the renal pelvis and ureter. pyelonephritis. Therefore, when EACA is used, the patient

URINARY TRACT INFECTION due to hyperfiltration, glomerulopathy, and glomerular capillary hypertension. Asymptomatic bacteriuria and symptomatic Nephrotic syndrome associated with a urinary tract infections are common in sick- Archivemembranoproliferative glomerulonephritis le cell disease patients. Radiologic changes has been described in patients with SS dis- are often difficult to differentiate from interstitialfor nephritis historical due to ischemia or Referenceease. If proteinuria Only persists for more than 4 analgesic nephropathy. weeks, it should be evaluated with 24-hour urinary protein quantitation and creatinine Because women with sickle cell disease clearance. In the presence of prenephrosis may be at greater risk for pyelonephritis, (24-hour urine protein > 2.0 g/24 hrs or frequent urinalyses and periodic urine cul- nephrotic syndrome (protein > 3.0/24 hrs, tures with colony counts may be useful as hypoalbuminemia, hyperlipidemia, and a routine surveillance measure. Significant edema), the patient should be referred to a 5 bacteriuria (> 10 /mL) and documented nephrologist for evaluation and possible pyelonephritis should be treated with renal biopsy. When biopsies are done, appropriate antibiotic therapy, and repeat pathologic examination should include cultures should be obtained to confirm immunohistology (IgG, C1, IgM, and anti- “sterilization” of the urine. Initiation of renal tubular epithelial antigen) and elec- antibiotic therapy with trimethoprim-sulfa tron microscopy to establish the histologic or ampicillin is recommended; on the basis diagnosis. of culture and sensitivity data, therapy should then be modified. Blood cultures HYPERTENSION should be obtained on febrile patients with suspected pyelonephritis. Individuals who Persistent elevation of diastolic blood pres- have had a single bout of pyelonephritis sure in patients with sickle cell disease should have careful long-term monitoring, usually signals underlying renal disease. It including repeat urinalyses, cultures, and occurs in fewer than 5 percent of individu- renal function studies. With an initial bout als with sickling disorders and increases of pyelonephritis or with recurrence in a with advancing age. Although the hyper- previously unstudied patient, an IVP should tension appears to be renoprival in nature, be done, possibly in consultation with a plasma renin levels are variable. Evaluation urologist, to exclude a predisposing or of hypertension in the patient with sickle resultant anatomic defect in the urinary cell disease is the same as in other individ- tract. In children, a voiding cystourethrogram uals. Transient hypertension may occur may be indicated. Patients with persistent during painful episodes and following red or recurrent pyelonephritis should be con- blood cell transfusions. sidered for long-term antibiotic therapy Therapy for hypertension in patients with (see Chapter 6, Infection). sickling disorders differs from that used for other individuals. Diuretics generally are to PROTEINURIA AND NEPHROTIC be used with caution, particularly in SYNDROME younger patients because dehydration may Approximately 25 percent of adult patients provoke a vaso-occlusive crisis. The natri- with SS disease have chronic proteinuria uretic response to loop diuretics is

decreased, particularly in older patients. balance should be carefully monitored. Initial therapy with beta-adrenergic block- Drugs with altered pharmacokinetics in the ers or calcium channel inhibitors is pre- presence of renal failure should either be ferred, and theArchive dosage must be individual- avoided or have dosages appropriately ized. In hypertensive patients with signifi- modified. As renal failure progresses, the cant proteinuria, angiotensin-converting patient should be referred for dialysis or enzymefor inhibitors historical may both control Reference hyper- possible Onlyrenal transplantation. tension and reduce proteinuria by decreas- Sickle cell disease is not a contraindication ing glomerular capillary hypertension. for hemodialysis or renal transplantation. Due to the compensatory alterations of car- Sickle cell disease patients who have diovascular function in sickle cell disease received renal homografts may experience patients, the deleterious effects of hyper- more frequent pain crises due to increased tension on the heart and vascular system hematocrit driven by erythropoietin pro- are likely to be amplified. When congestive duced by the graft kidney. Recurrent sickle heart failure is present in the hypertensive cell nephropathy in the transplanted kidney sickle cell patient, afterload reduction ther- has been reported. apy is indicated. Because the risk of stroke In some patients, the increased anemia is increased in sickle cell disease and arter- found with chronic renal failure causes car- ial aneurysms of the circle of Willis may diopulmonary complications and necessi- appear as early as the second decade, tates a chronic transfusion program. effective control of blood pressure is Treatment with recombinant erythropoietin imperative. (EPO) improves the anemia of renal failure in nonsickle cell disease patients; howev- CHRONIC RENAL FAILURE er, there are no large studies of the use of Chronic renal failure in sickle cell disease EPO in Hb SS patients with renal failure. is associated with end-stage renal disease The experience with a few of these patients due to one or a combination of the sickle so far indicates that large doses of EPO cell nephropathies discussed above. (300 - 350 U/kg three times a week) may Chronic renal failure occurs in a small per- be required to induce a significant increase centage of patients with sickling disorders, in hematocrit or to alleviate a transfusion and its prevalence in sickle cell disease requirement. appears to be greater than among the general African-American population. When BIBLIOGRAPHY it is associated with metabolic acidosis Allon M. Renal abnormalities in sickle cell without significant hyperkalemia and with disease. Arch Intern Med 1990;150:501-4. BUN levels less than 80.0 mg/mL and creatinine less than 4.0 mg/mL, patients can Bakir AA, Hathiwala SC, Ainis H, et al. usually be managed with conservative mea- Prognosis of the nephrotic syndrome in sures, including oral sodium bicarbonate, sickle glomerulopathy. A retrospective oral phosphate binders such as Amphojel, study. Am J Nephrol 1987;7:110-5. and a low-protein diet. In this instance, Falk RJ, Jennette JC. Sickle cell nephropa- BUN, creatinine, electrolytes, and acid-base thy. Adv Nephrol 1994:23:133-47.

Falk RJ, Scheinman J, Phillips G, et al. Powars DR, Elliott-Mills DD, Chan L, et al. Prevalence and pathologic features of Chronic renal failure in sickle cell disease: sickle cell nephropathy and response to risk factors, clinical course and mortality. inhibition of angiotensive-convertingArchiveAnn Intern Med 1991;115:614-20. enzyme. N Engl J Med 1992;326:910-5. Sherwood JB, Goldwasser E, Chilcote R, Johnson forCS, Giorgio historical AL. Arterial blood ReferenceCarmichael LD, Only Nagel RL. Sickle cell ane- pressure in adults with sickle cell disease. mia patients have low erythropoietin levels Arch Intern Med 1981;141:891-3. for their degree of anemia. Blood 1986;67:46-9. Miner DJ, Jorkasky DK, Perloff LJ, Grossman RA, Tomaszewski JE. Recurrent Steinberg MH. Erythropoietin for anemia of sickle cell nephropathy in a transplanted renal failure in sickle cell disease. N Engl J kidney. Am J Kidney Dis 1987;4:306-13. Med 1991;324:1369. Pardo V, Strauss J, Kramer H, Ozawa T, Thompson A, Lessin L, Antonovych T. The MacIntosh R. Nephropathy associated with sickle cell nephropathies. In: Fried W (ed). sickle cell anemia: an autologous immune Comparative clinical aspects of sickle cell complex nephritis. I. Clinicopathologic disease. New York: Elsevier, 1982. study of seven patients. Am J Med 1975;59:650-9.

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CHAPTER 19 PRIAPISMArchive for historical Reference Only

Priapism is a persistent, painful penile erec- CHRONIC PRIAPISM tion. Three clinical categories are discussed This is a rare form of presentation that may in this chapter, including recurrent acute follow an acute episode or may arise de priapism, acute prolonged priapism, and novo. The penis is semierect and there is chronic priapism. no pain. Clinically, this results in a progressive increase in the size of the penis, and RECURRENT ACUTE PRIAPISM penile scan shows good blood flow. Penile This is the most common form of priapism ultrasound shows dilated deep dorsal arter- in which the patient gets short attacks that ies in both corporeal bodies, and the subside spontaneously. The patient usually patient has difficulty in getting a complete copes with this problem and may not seek erection. Occasionally these patients may medical advice. The natural history is vari- develop an acute episode. Suddenly for no able. Most patients will continue to get apparent reason the penis becomes rigid attacks throughout their lives and will and painful. These episodes may affect maintain some degree of potency. Others only a part of the penile shaft. will eventually become impotent. A small group will develop an acute attack that will PATHOPHYSIOLOGY not subside without active and aggressive The specific mechanisms that precipitate treatment in a timely fashion. attacks of acute priapism in patients with sickle cell disease are unknown. Acute ACUTE PROLONGED PRIAPISM attacks often start during sleep, occasional- The painful erection that does not subside ly following sexual activity, but frequently after several hours is an emergency and no identifiable event is noted. An unusually should be treated aggressively. If untreated, full bladder is commonly associated with the attack will last for several weeks, result- the onset of nocturnal attacks. Some ing in total impotence. Even with aggres- episodes appear to be triggered or exacer- sive treatment, preservation of potency may bated by dehydration. be compromised. The presenting features Some patients with priapism have preserva- are persistent erection, severe pain, and tion of flow to the glans and spongiosal tis- tenderness of the penile shaft. Radionuclear sue. Venous outflow from the corpora cav- penile scan may show a very low flow, ernosa is not always totally occluded as and penile blood gas may have a pO2 of had been earlier postulated. These facts less than 5. establish the rationale for transfusing

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normal red cells because these cells can be Acute Prolonged Priapism expected to gradually reach areas of poor Possible etiologies for this pattern should circulation. Alternatively some patients may be sought. These include infection (particu- have tricorporal priapism,Archive which is more larly of the prostate), recent trauma, med- severe. ications with autonomic effects, alcohol Presumably,for a viscous historical mass of deoxygenat- Referenceexcess, marijuana Only use, or sexual activity. ed and damaged red cells develops that Initial treatment of acute, prolonged pri- further impairs or occludes outflow. Edema apism should include rigorous intravenous and inflammation can result. Evacuation of hydration, parenteral narcotics to relieve this material can delay irreversible damage pain, and if necessary, insertion of a Foley to the corpora cavernosa. Hemoglobin catheter to promote bladder emptying. In electrophoresis of penile blood in trans- addition, preparations should be made to fused patients occasionally shows that no reduce the percentage of sickle cells to less Hb A has entered the corpora cavernosa. than 30 percent while maintaining the These observations establish the rationale hematocrit below 35 percent. This objective for aspiration and irrigation and for the can most effectively be accomplished by temporary corpora spongiosum shunt exchange transfusion. Patients who are procedure currently in use (see Winter likely to respond to transfusion regimens procedure below). begin detumescence within 1 or 2 days, although complete detumescence may take GENERAL MANAGEMENT weeks to months. There are reports of The goals of management are to assist with cerebrovascular hemorrhage in children fol- emptying the corpora cavernosa, relieve lowing exchange transfusions for priapism. the patient’s pain, and, if possible, prevent Concepts in the surgical treatment of impotence. As with other inflammatory severe priapism in sickle cell disease are events in sickle cell disease, fever and currently changing toward a simpler proce- leukocytosis can occur in the absence of dure and much earlier intervention. infection. Nevertheless, infectious etiologies Opinion is not yet uniform, but recent should be ruled out. studies suggest that if detumescence has not begun within 24 hours following com- Recurrent Acute Priapism pletion of transfusion therapy, a significant Patients often manage this condition at response to transfusion alone is unlikely. In home. Emptying the bladder, warm baths, this case, a penile aspiration should be and exercise are all recommended tech- tried first; if this is not successful, a Winter niques. The patient should be encouraged procedure (spongiosum-cavernosum shunt) to empty the bladder frequently once the or a Hashmat shunt are recommended attack has begun. At the same time, how- under local anesthesia in adults or, prefer- ever, the patient should be encouraged to ably, general anesthesia in children. A increase oral intake of fluid to offset any saphenous shunt is no longer recommended. possible contribution of systemic dehydra- Despite interventions, impotence remains a tion. If the episode does not resolve in 3 frequent complication of priapism. For hours, the patient should seek medical incapacitating recurrent priapism, a trial of attention.

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chronic transfusions for 3 to 6 months is Hamre MR, Harmon EP, Kirkpatrick DV, et often successful. al. Priapism as a complication of sickle cell disease. J Urol 1991;145:1-5. MANAGEMENTArchive OF IMPOTENCE Hashmat AI, Das S. The penis. Philadelphia: Although the patient is not suffering with Lea and Febiger, 1993. pain,for erectile historical function is often absent Reference or Hashmat Only AI, Samanthi R, Singh I, Macchia impaired. Management of impotence by R. 99m Tc penile scan: an investigative implantation of a prosthesis has been per- modality in priapism. Urol Radiol formed by some urologists. Other patients, 1989;11:58-60. however, are able to adjust to the altered sexual function, usually with the support of Noe HN, Wilimas J, Jerkins GR. Surgical an accommodating partner, because ejacu- management of priapism in children with lation, orgasm, and fertility remain intact. sickle cell anemia. J Urol 1981;126(6):770-1. Surgical intervention is rarely needed in Rackoff WR, Ohene-Frempong K, Month S, prepubertal boys. Scott JP, Neahring B, Cohen AR. Neurologic events after partial exchange transfusion for BIBLIOGRAPHY priapism in sickle cell disease. J Pediatr Bertram RA, Webster GD, Carson CC. 1992;120:882-5. Priapism: etiology, treatment, and results in Sharpsteen JR Jr, Powars D, Johnson C, series of 35 presentations. Urology Rogers ZR, Williams WD, Posch RJ. 1985;26:229-32. Multisystem damage associated with tricor- Emond AM, Holman R, Hayes RJ, Serjeant poral priapism in sickle cell disease. Am J GR. Priapism and impotence in homozy- Med 1993;94:289-95. gous sickle cell disease. Arch Intern Med Winter CC. Priapism cured by creation of 1980;140(11):143-47. fistule between glans penis and corpora cavernosa. J Urol 1980;423:595-6.

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Archive for historical Reference Only

CHAPTER 20 HEART Archive for historical Reference Only

The anemia of SS disease is usually well unusual in patients with sickle cell disease. tolerated by the cardiovascular system for However, symptoms such as dyspnea, pal- long periods. However, like other moder- pitations, and easy fatigability frequently ately severe anemias, cardiac function is seen in these patients may lead to clinical ultimately affected. Physicians caring for misdiagnosis of heart failure. Without docu- patients with SS disease should be aware mented evidence of failure, treatment of of cardiovascular involvement in these symptoms with digitalis and diuretics is not patients because the physician may be con- indicated, and transfusion should be con- fronted with a variety of symptoms and sidered if the hemoglobin concentration is physical findings similar to ventricular quite low. Right ventricular enlargement is abnormalities, valvular dysfunction, and less common and usually occurs in patients myocardial ischemia, which pose diagnostic with pulmonary hypertension, which is a and therapeutic difficulties. consequence of recurrent pulmonary artery thrombosis. CARDIAC FUNCTION CHILDREN The reduced oxygen-carrying capacity due to anemia increases demand on the heart Insights into the adaptation of children and with an increased cardiac output. This adolescents to chronic anemia have been chronic volume overload initiates compen- gleaned primarily from echocardiographic satory responses, primarily cardiac enlarge- studies. Children with SS disease and ment. Although both dilation and hypertro- hemoglobin levels in the range of 6 to 8 phy frequently occur, systolic and diastolic g/dl increase cardiac output at rest by 50 performance of the left ventricle in the percent to meet the need for oxygen deliv- resting state is usually preserved. However, ery to the tissues. This increase is achieved with radionuclide imaging studies and primarily through larger stroke volume, echocardiographic-derived indices, abnor- which results in the clinical findings of malities in contraction and relaxation may hyperdynamic circulation, heart murmur, be identified. In patients with these abnor- and cardiomegaly. Cardiomegaly is a malities, reduced peripheral vascular resis- healthy adaptation to anemia and should tance maintains normal left ventricular sys- not by itself be considered pathologic. Few tolic performance (as measured by ejection children develop congestive heart failure in fraction). the absence of a sudden and profound In the absence of coexistent cardiovascular decrease in hemoglobin concentration. disease, overt left ventricular failure is Correction of severe anemia may require

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exchange blood transfusion (see Chapter exercise testing develop S-T-segment 10, Transfusion). Most children and adoles- depression on EKG, which appears to cents with sickle cell anemia successfully relate to older age, low level of hemoglo- adapt to the increasedArchive cardiac demands bin, and the product of heart rate and sys- posed by chronic anemia and usually have tolic blood pressure. As described in chil- a reduced exercise capacity of 50 to 75 dren, these changes are due to subendo- percent offor that ofhistorical unaffected children. Referencecardial ischemia Only but are not associated with Unlike adults, they are less likely to admit pain. Atherosclerotic coronary obstruction to exercise intolerance. is unlikely to be the cause. Because there is no evidence that exercise For patients seeking advice on exercise, is harmful, and the beneficial effects of participation in noncompetitive recreational exercise are well known, children with activities should not be discouraged. sickle cell disease are encouraged to partic- However, exercise should not be per- ipate in physical activities and to set their formed to the point of exhaustion. The own limits. If exercise-related symptoms same general principle applies to work; occur, they should be evaluated with exer- that is, employment requiring a modest but cise electrocardiography. Fifteen percent not an exhausting degree of exertion is of adolescents performing exercise stress acceptable. Specific recommendations for tests develop S-T depression on electrocar- conditioning exercise or training cannot be diogram due to subendocardial ischemia. made at this time because of lack of avail- It is important to remember that children able data. Exercise under adverse condi- with SS disease are subject to the same tions, for example, cold weather, high alti- medical conditions as other children, and tude, or cold water exposure, should be findings that might suggest congenital, avoided. rheumatic, or other underlying heart disease should be investigated. In such Valvular cases, heart function is most reliably Systolic murmurs are common in patients assessed by echocardiography and a with SS disease, are usually best heard in cardiology consultation. the second and third intercostal spaces, and are a consequence of the increased ADULTS cardiac output. However, basal diastolic murmurs are rare and should be consid- Exercise Performance ered pathologic when present. Structural Exercise capacity is reduced in most valvular deformities do not appear to be patients with SS disease. Most are able to increased in this disease. The prevalence of achieve less than 50 percent of maximum mitral valve prolapse has been reported to predicted workloads. The cause for this be high in patients with SS disease; howev- decreased physical performance is likely er, this finding was not confirmed by the multifactorial, and the role of cardiac Special Cardiac Study of the Cooperative dysfunction in this reduced work capacity Study of the Clinical Course of Sickle Cell is unclear. A significant number of these Disease. patients undergoing symptom-limited

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Diagnostic Testing these patients is remarkable for the absence of significant atherosclerosis. ■ Doppler echocardiography is recom- However, a postmortem study of 70 mended to assess a cardiac murmur Archivepatients with SS disease revealed that 17 suspected to be pathologic in origin. percent had myocardial infarction or fibro- ■ Resting and stress cardiac imaging stud- sis despite normal coronary arteries. iesfor (radionuclide historical or echocardiographic) ReferenceRecently, Only a group of patients with acute are useful in determining cardiac cham- chest pain during sickle cell pain crisis was ber dimensions and global systolic func- described with clinical evidence of myocar- tion of both right and left ventricles. dial ischemia or infarction. The role of red ■ The utility of exercise testing in patients cell sickling in the pathogenesis of this with exercise-induced chest pain is limit- phenomenon is unclear. Coronary spasm, ed because exercise-induced EKG as a secondary event of sickling, has been changes may not represent coronary suggested as a mechanism. Although coro- obstructive disease. In individuals sus- nary insufficiency is rare in patients with pected of having coronary artery disease, sickle cell disease, an electrocardiogram this procedure should be supplemented and cardiac enzymes should be obtained with thallium myocardial perfusion on all adult patients hospitalized with vaso- scanning or dobutamine stress occlusive episodes and chest pain sugges- echocardiography. tive of myocardial ischemia or infarction. Sickle cell anemia is normally associated ■ Cardiac catheterization using contrast with dilated coronary arteries free of ather- media has been performed safely in osclerotic plaque; however, newer diagnos- small numbers of patients with SS dis- tic tests suggest that this does not preclude ease after partial exchange transfusion. the development of myocardial ischemia or Experience with this invasive procedure infarction. in sickle cell disease is limited and should be reserved for those patients in BIBLIOGRAPHY whom there is a high index of suspicion for the diagnosis of significant epicardial Alpert BS, Gilman PA, Strong WB, et al. coronary artery disease and whose car- Hemodynamic and ECG responses to exer- diac status cannot be satisfactorily evalu- cise in children with sickle cell anemia. Am ated by noninvasive testing. Dehydration J Dis Child 1981;135:362-6. resulting from the diuretic effect of the Balfour IC, Covitz W, Arensman FW, et al. hypertonic contrast media must be Left ventricular filling in sickle cell anemia. avoided. Use of nonionic contrast mater- Am J Cardiol 1988;61:395-9. ial may prevent this complication. Balfour IC, Covitz W, Davis H, et al. Cardiac size and function in children with Myocardial Infarction sickle cell anemia. Am Heart J Clinical and autopsy studies in adult 1984;108:345-50. patients demonstrate the infrequent occur- Covitz W. Cardiac disease. In: Embury S, rence of myocardial infarction in individu- Hebbel RP, Mohandas N, Steinberg MH als with SS disease. Coronary anatomy in (eds). Sickle cell disease: basic principles

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and clinical practice. New York: Raven cell anemia. J Am Coll Cardiol Press, 1994:725-34. 1991;17:1473-8. Covitz W, Eubig C, ArchiveBalfour IC, et al. Miller GJ, Serjeant GR, Sivapragasam S, Exercise-induced cardiac dysfunction in Petch MC. Cardiopulmonary responses and sickle cell anemia. Am J Cardiol gas exchange during exercise in adults 1983;51:570-5.for historical Referencewith homozygous Only sickle cell disease (sickle cell anemia). Clin Sci 1973;44:113-28. Denenberg BS, Criner G, Jones R, Spann JF. Cardiac function in sickle cell anemia. Am J Norris S, Johnson CS, Haywood TJ. Sickle Cardiol 1985;51:1674. cell anemia: does myocardial ischemia occur during crisis? J Natl Med Assoc Gerry JL, Baird MG, Fortuin NJ. Evaluation 1991;83:209-13. of left ventricular function in patients with sickle cell anemia. Am J Med 1976;60:968- O’Neill B Jr, Saunders DE, McFarland DE, 72. O’Neal H. Myocardial infarction in sickle cell anemia. Am J Hematol 1984;16:139-47. Gerry JL, Buckley BH, Hutchins GM. Clinicopathologic analysis of cardiac dys- Simmons BE, Santhanson V, Castaner A, et function in 52 patients with sickle cell ane- al. Sickle cell heart disease. Two dimen- mia. Am J Cardiol 1978;42:211-6. sional echo and Doppler ultrasonographic findings in the hearts of adult patients with Lewis JT, Maron BJ, Castro O, Moosa Y. sickle cell anemia. Arch Intern Med Left ventricular diastolic filling abnormali- 1988;148:1526-8. ties identified by Doppler echocardiography in asymptomatic patients with sickle

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CHAPTER 21 SURGERYArchive AND ANESTHESIA for historical Reference Only

Patients with sickle cell disease who under- TYPES OF SURGERY go surgery have an increased risk of peri- Surgical procedures that have an increased operative complications. Careful preopera- probability of ischemia or hypoxia deserve tive preparation of the patient by a team special attention. These include cardio- consisting of a surgeon, hematologist, and thoracic surgery; techniques associated anesthesiologist will minimize or eliminate with hypotension, hypothermia, and these complications. hyperventilation; and vascular surgery. PREEXISTING HEALTH OF THE Laparascopic surgery appears to lower the PATIENT postoperative complications of sickle cell disease and should be used in appropriate Patients with organ damage and/or coexis- settings. tent disease must be identified because they are at increased risk for perioperative PREOPERATIVE CARE complications. All patients should be evaluated by the In particular, older patients, those with a anesthesiologist the day before surgery. history of pulmonary or CNS disease, recur- Patients requiring general anesthesia should rent hospitalizations, and/or those who receive maintenance fluids at least 12 hours have been previously heavily transfused before surgery, with strict attention paid to are at high risk for perioperative complica- urinary output and weight. Preoperative tions, especially acute chest syndrome and assessment of the patient should include vaso-occlusive events. A physical examina- checking for signs of vaso-occlusion, fever, tion and chart review should be supple- infection, and dehydration. The laboratory mented by the following tests: and physical examination results should be ■ Arterial oxygen pressure or oxygen satu- reviewed to identify abnormalities in the ration measured by pulse oximetry. heart, liver, kidneys, brain, and lungs. ■ Pulmonary function tests with bron- chodilator response analysis for patients INTRAOPERATIVE MANAGEMENT who have acute chest syndrome, asthma, All patients should be monitored with at or other pulmonary complications. least an EKG and have a determination of ■ Echocardiogram. inspired oxygen concentration by pulse oximetry or blood gas testing. ■ Renal and liver functions. Measurements of electrolyte and urine output and invasive hemodynamic monitors

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may be required, depending on the Esseltine DW, Baxter M, Bevan JC. Sickle patient’s clinical status and the type of cell states and the anesthesiologist. Can J surgery. A warm temperature should be Anaesth 1988;35:385-403. maintained in the operatingArchive room. General Fullerton MW, Philippart AI, Sarnaik S, anesthesia should aim for a mild respirato- Lusher J. Preoperative exchange transfusion ry alkalosisfor (pH historicalabout 7.45) and a nor- Referencein sickle cell anemia.Only J Ped Surg mothermic, well-hydrated patient. The 1981;16:297-300. patient should receive a minimum of 50 percent oxygen in combination with the Gibson J. Anesthesia for sickle cell disease anesthetic agent. Blood replacement for and other hemoglobinopathies. Semin significant intraoperative blood loss is rec- Anesth 1987;6:27-35. ommended. Intraoperative blood salvage Homi J. General anesthesia in sickle cell techniques (cell savers) are not disease. Br Med J 1979;1:1599-1601. recommended. Janik J, Seeler RA. Perioperative manage- Postoperatively, oxygen should be adminis- ment of children with sickle hemoglo- tered until the effects of anesthesia have binopathy. J Pediatr Surg 1980;15:117-20. worn off. Patients who have surgical Koshy M, Weiner SJ, Miller ST, et al. wounds that interfere with respiration may Surgery and anesthesia in sickle cell dis- require an extended use of oxygen. ease. Blood 1995;86(10). Continued monitoring by oximetry is recommended in the recovery room and/or National Institutes of Health. NIH intensive care unit. Postoperative parenteral Consensus Development Conference hydration should keep the patient at 1 to Statement From Perioperative Red Cell 1½ times maintenance. Aggressive respira- Transfusion. Vol. 7, No. 4, June 27-29, tory care is necessary in sickle cell disease 1988. to minimize pulmonary complications. Searle JF. Anesthesia in sickle states. Anaesthesia 1973;28:48-58. BIBLIOGRAPHY Vichinsky EP, Haberkern CM, Neumayr L, Bischoff RJ, Williamson A III, Dalali MJ, et et al. A comparison of conservative and al. Assessment of the use of transfusion aggressive transfusion regimens in the peri- therapy perioperatively in patients with operative management of sickle cell dis- sickle cell hemoglobinopathies. Ann Surg ease. N Engl J Med 1995;333(4):206-13. 1988;207:434-8. Ware R, Filston HC, Schultz WH, Kinney Burrington JD. Elective and emergency TR. Elective cholecystectomy in children surgery in children with sickle cell disease. with sickle hemoglobinopathies: successful Surg Clin North Am 1976;56:55-71. outcome using preoperative transfusion regimen. Ann Surg 1988;208:17-35.

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CHAPTER 22 SICKLE CELLArchiveTRAIT for historical Reference Only

Sickle cell trait is not a disease. It is not a sickle cell trait must be evaluated thor- cause for abnormalities in the blood count oughly to exclude other causes, as in other and does not produce vaso-occlusive patients. Traumatic hyphema in individuals symptoms under physiologic conditions. with sickle cell trait requires special man- Sickle cell trait does not adversely affect agement (see Chapter 12, Eye). the individual’s life expectancy. When individuals with sickle cell trait Sickle cell trait (AS) is a heterozygous con- become hypoxic, they rarely develop dition in which the individual has one symptoms related to vaso-occlusion. A betaS gene and one betaA globin gene, recent retrospective study of military resulting in the production of both Hb S recruits showed an increased risk of sud- and Hb A with a predominance of Hb A. den death following extreme exertion dur- Sickle cell trait is found in 8 percent of the ing basic training in soldiers with sickle cell American Black population. The diagnosis trait compared with individuals with only should be established by hemoglobin elec- Hb A. The magnitude of the increased risk trophoresis. Persons who have more Hb S was very small (32 per 100,000 compared than Hb A on electrophoresis (and have with 1 per 100,000 for recruits with Black not been transfused) have Hb Sβ+ thal and parents who had normal hemoglobin) and not sickle cell trait. appeared to be related to the recruit’s age. Hemoglobin electrophoresis is used to No increased risk of sudden death has screen persons for sickle cell trait and will been reported in civilians, including those also detect persons with sickle cell disease who participate in athletics. Changes in and heterozygotes (carriers) for other training programs for recruits seem to have hemoglobin disorders such as Hb C. Like reduced the problem of sudden death dur- sickle cell trait, hemoglobin C trait pro- ing basic military training. There appears to duces no hematologic abnormalities aside be no increased risk for individuals with from a few target cells on blood smears. sickle cell trait who undergo general anes- Hemoglobin C trait is not detected by solu- thesia. However, splenic infarction has bility testing or by a sickle cell preparation. been reported as a result of flying above 15,000 feet in unpressurized aircraft. Sickle cell trait has been associated with several clinical conditions, including hypos- Individuals with sickle cell trait should thenuria, painless hematuria, and an receive informative and nondirective genet- increased risk of urinary tract infection dur- ic counseling. Before counseling couples, it ing pregnancy. Hematuria in persons with is important to perform hemoglobin

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electrophoresis and Hb A2 and Hb F mea- Kark JA, Posey DM, Schumaeker HR, surements on both prospective parents. In Ruehle CJ. Sickle cell trait as a risk factor parents who are not carriers of an abnor- for sudden death in physical training. N mal hemoglobin, measurementsArchive of Hb A2 Engl J Med 1987;317:781-7. and Hb F are needed to identify thal- Lane PA, Githens JH. Splenic syndrome at assemic conditions.for historical When both parents Referencemountain altitudes Only in sickle cell trait: its have sickle cell trait, they have a 25 per- occurrence in nonblack persons. JAMA cent chance with each pregnancy of having 1985;253:2251-4. a child with SS disease. If one parent has sickle cell trait and the other has a beta McInnes BX III. The management of hema- thalassemic disorder, they are at the same turia associated with sickle hemoglo- risk for having a child with a sickle beta binopathies. J Urol 1980;124:171-4. thalassemia syndrome. In couples where Monplaisir N, Merault G, Poyart C, et al. one individual has sickle cell trait and one Hemoglobin S Antilles: a variant with lower has hemoglobin C trait, the chance of hav- solubility than hemoglobin S and producing a child with Hb SC disease is also 25 ing sickle cell disease in heterozygotes. percent with each pregnancy. If one parent Proc Nat Acad Sci USA 1986;83:9363-7. has SS disease and the other has sickle cell trait, the risk of having a child with SS dis- Pritchard JA, Scott DF, Whalley PJ. The ease is 50 percent with each pregnancy effects of maternal sickle cell hemoglo- (see Chapter 14, Prenatal Diagnosis, for binopathies and sickle cell trait on repro- further discussion). ductive performance. Am J Obstet Gynecol 1973;117:662-70. In rare cases, individuals thought to have sickle cell trait subsequently were shown to Sears DA. The morbidity of sickle trait: a have sickle hemoglobin plus another review of the literature. Am J Med hemoglobin variant. In at least one instance 1978;64:1021-36. (Hb S-Antilles), the “S” molecule actually Witkowska E, Lubin B, Beuzard, et al. had two amino acid substitutes in the same Sickle cell disease in a patient with sickle β chain. Thus, in cases where symptoms cell trait and compound heterozygosity for occur in an individual thought to have hemoglobin S and hemoglobin Quebec- sickle cell trait, careful confirmation of lab- Chori. N Engl J Med 1991;325:1150-4. oratory diagnosis is essential.

BIBLIOGRAPHY Eichner ER. Sickle cell trait, exercise, and altitude. Physician Sports Med 1986;14:144- 57.

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CHAPTER 23 EXPERIMENTALArchiveTHERAPY for historical Reference Only

The lifespan of patients with SS disease has disease or Sβ thal. The mechanism of increased significantly in the past 30 to 40 action is still unclear but probably involves years, partly because of improvements in altered proliferation of early red blood cell the general health of all citizens and thera- precursors capable of increased Hb F syn- peutic approaches described in earlier thesis. A double-blind multicenter trial has chapters. Today, the median survival of Hb recently concluded that use of the drug can SS patients is about 45 years. Further reduce the frequency of painful episodes improvements in the quality of life and of by almost 50 percent. With long-term risks the lifespan will come from treatments poorly understood, the caveats described such as penicillin prophylaxis and others above should be followed. Other drugs that must be considered experimental at such as erythropoietin and butyrate the present time. Faced with severely ill derivatives may be capable of augmenting patients who have the most to gain and the Hb F production by other means. Their least to lose from experimental therapy, role in therapy, alone or combined with health providers and patients must consider hydroxyurea, is still unclear. the options available. Patients should be involved in a therapeutic trial whenever BONE MARROW possible. In all cases, patients must be TRANSPLANTATION carefully informed of potential risks and Successful bone marrow transplantation benefits of the proposed therapy. can cure sickle cell anemia, and initial Treatment should be carried out by physi- reports from Europe suggest that transplan- cians with experience in sickle cell disease, tation can be carried out with relatively the use of the therapy involved, and in the low morbidity and mortality. Most investi- conduct of experimental therapeutic trials. gators agree that transplantation should be considered for severely affected children; HYDROXYUREA the dilemma is that severely affected Fetal hemoglobin (Hb F) interferes with the patients are poor risks for an arduous pro- polymerization of Hb S in solution and cedure. At present, unrelated donors with the sickling of Hb SS red blood cells. should not be used, and the availability of Hydroxyurea, a cytotoxic chemotherapeutic compatible sibling donors is limited. A agent, was shown to augment Hb F pro- national collaborative study of transplanta- duction in SS patients in a preliminary trial, tion in pediatric patients in the United without serious toxicity. To date, no trials States, with strictly defined criteria for eligi- have been carried out in patients with SC bility, is currently under way; preliminary

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results are somewhat encouraging. that new treatments are under active investi- Umbilical cord blood may prove to be an gation may make that burden somewhat important resource for stem cell transplanta- lighter and provide them with reason to hope. tion in sickle cell disease.Archive BIBLIOGRAPHY It is hoped that such studies will permit a definitionfor of risk historical factors and improved Referenceeli- Adams RJ, McKie Only V, Nichols FT, et al. The gibility criteria for bone marrow transplan- use of transcranial ultrasonography to pre- tation in Hb SS patients just as risk factors dict stroke in sickle cell disease. N Engl J and eligibility criteria for bone marrow Med 1992;326:605-10. transplantation have been defined for Castro O, Brambilla DJ, Thorington B, et al. patients with thalassemia major. Cost-bene- The acute chest syndrome in sickle cell dis- fit analyses, in terms of health and well- ease: incidence and risk factors. The being of patients and financial outlays for Cooperative Study of Sickle Cell Disease. individual patients and for society as a Blood 1994;84:643-9. whole, also will emerge from this ongoing research. Charache S, Terrin ML, Moore RD, et al. Effects of hydroxyurea on the frequency of PROPHYLACTIC TRANSFUSION TO painful crises in sickle cell anemia. N Engl J PREVENT STROKE Med 1995;332:1317-20. Transcranial Doppler studies can demon- Johnson FL, Mentzer WC, Kalinyak KA, et strate arterial narrowing in SS patients who al. Bone marrow transplantation for sickle subsequently have strokes. A randomized cell disease: the United States experience. trial is currently under way to determine Am J Pediatr Hematol Oncol 1994;16:22-6. whether chronic transfusion therapy can Platt OS, Brambilla DJ, Rosse WF, et al. prevent first strokes in children with Mortality in sickle cell disease. Life abnormal Doppler studies. expectancy and risk factors for early death. N Engl J Med 1994;330:1639-44. GENETIC ENGINEERING Platt OS, Thorington BD, Brambilla DJ, et Once fanciful, gene therapy now seems a al. Pain in sickle cell disease: rates and risk very possible future development. Basic factors. N Engl J Med 1991;325:11-6. laboratory studies are under way, but it appears unlikely that application to patients Vermylen C, Cornu G. Bone marrow trans- will be possible for a number of years. plantation for sickle cell disease: the European experience. Am J Pediatr IMPORTANCE OF ONGOING Hematol Oncol 1994;16:18-21. CLINICAL RESEARCH Vichinsky EP, Lubin BH. A cautionary note The foregoing chapters reaffirm that our regarding hydroxyurea in sickle cell dis- current therapy provides patients with sick- ease. Blood 1994;83:1124-8. le cell disease some solace but not enough Walters MC, Bernaudin F, Johnson FL, et al. to prevent an uncertain future. Most of our Neurologic complications following allo- patients and their families know the current geneic bone marrow transplantation for therapeutic limitations; however, knowledge sickle cell anemia. Blood 1993;82(suppl 1):417a.

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Archive for historical Reference Only

115 Division of Blood Diseases and Resources ainlHat ug andBloodInstitute Lung, National Heart,

M ANAGEMENT

Archive AND THERAPY OF for historical Reference Only SICKLE CELL DISEASE M NGMN AND ANAGEMENT T EAYOF HERAPY S ICKLE C ELL D ISEASE

U.S. DEPARTMENT OF HEALTH AND

HUMAN SERVICES 1995

Public Health Service National Institutes of Health NATIONAL INSTITUTES OF HEALTH NIH Publication No. 95-2117 December 1995 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE